Sodium thiosulfate-containing pharmaceutical compositions

ABSTRACT

Provided herein are pharmaceutically acceptable sodium thiosulfate and pharmaceutical compositions thereof. Also provided herein are methods for determining the total non-purgeable organic carbon in a sodium thiosulfate-containing sample. Further provided herein are methods for producing pharmaceutically acceptable sodium thiosulfate. Still further provided herein are methods of treatment comprising the administration of pharmaceutically acceptable sodium thiosulfate.

This application is a continuation of U.S. patent application Ser. No.13/927,241, filed Jun. 26, 2013, currently allowed, which is acontinuation of U.S. patent application Ser. No. 12/831,331, filed Jul.7, 2010, now U.S. Pat. No. 8,496,973, issued Jul. 30, 2013, which claimsthe benefit of U.S. Provisional Patent Application No. 61/223,993, filedJul. 8, 2009, the entire contents of each of which are incorporatedherein by reference.

FIELD

Provided herein are pharmaceutically acceptable sodium thiosulfate (suchas sodium thiosulfate pentahydrate) and pharmaceutical compositionsthereof. Also provided herein are methods for determining the totalnon-purgeable organic carbon in a sodium thiosulfate-containing sample.Further provided herein are methods for producing pharmaceuticallyacceptable sodium thiosulfate. Still further provided herein are methodsof treatment comprising the administration of pharmaceuticallyacceptable sodium thiosulfate.

BACKGROUND

Sodium thiosulfate pentahydrate has numerous industrial applicationsincluding such uses as removing chlorine from solutions, bleaching paperpulp, and extracting silver from ores. It is also used as a fixer inphotography, a mordant in dyeing and printing textiles, and apharmaceutical ingredient. Even though thousands of metric tons ofsodium thiosulfate pentahydrate are produced annually, only a fewhundred kilograms are utilized pharmaceutically for the production ofsodium thiosulfate injection as currently indicated as a treatment forcyanide poisoning or for the production of a lotion containing sodiumthiosulfate pentahydrate for the treatment of tinea versicolor. It hasbeen recently reported that sodium thiosulfate pentahydrate is aneffective treatment for calciphylaxis (Ackermann et al., Archives ofDermatology 2007, 143(10): 1336-1337). It has also been reported thatsodium thiosulfate pentahydrate is an effective treatment for vascularcalcification (O'Neill, Kidney International 2008, 74(11): 1376-1378).It has been reported that sodium thiosulfate pentahydrate is aneffective treatment to prevent platinum-induced ototoxicity andnephrotoxicity that is associated with the use of platinum-containingchemotherapeutic agents (Skinner, Current Opinions in Oncology 1995,7(4): 310-315).

The manufacture of pharmaceutical products in the United States isregulated by the Food and Drug Administration (FDA). Since the passageof the Federal Food Drug and Cosmetic Act in 1938, the FDA has requirednew pharmaceutical products and their corresponding active ingredientsto be manufactured in accordance with the exacting requirements of“pharmaceutical grade” Good Manufacturing Practices as detailed in theUnited States Code of Federal Regulations 21 CFR 211. Because of therelatively small quantity of sodium thiosulfate pentahydrate that iscurrently used to formulate pharmaceutical products, no raw materialsupplier presently manufactures sodium thiosulfate pentahydrate inaccordance with “pharmaceutical grade” Good Manufacturing Practices.

In addition to regulating manufacturing practices, the FDA establishesstringent quality specifications for each new pharmaceutical product andits corresponding active ingredients. A pharmaceutical product isclassified as “new” if it was introduced to the market after the passageof the Food Drug and Cosmetic Act in 1938. As mandated in this Act, theFDA requires a new pharmaceutical product and its active ingredients tobe manufactured in accordance with “pharmaceutical grade” GoodManufacturing Practices and to meet applicable quality specifications.When the Food Drug and Cosmetic Act was enacted in 1938, pharmaceuticalsthat were already on the market were classified as “grandfathered drugs”and were permitted to remain on the market without formal FDA approvalif the product and its labeling remain unchanged. Any change to theproduct or its labeling would cause the “grandfathered drug” to become a“new” drug that is subject to FDA-imposed regulations and qualitystandards. Currently available sodium thiosulfate pentahydrate injectionthat is labeled solely for use as a treatment of cyanide poisoning andsodium thiosulfate pentahydrate-containing lotion that is labeled solelyfor use as a treatment of tinea versicolor are “grandfatheredmedications”. Consequently, the product formulations and correspondingquality specifications have remain unchanged for decades.

In anticipation of the receipt of a New Drug Application for a sodiumthiosulfate pentahydrate-containing pharmaceutical product, the FDArecently announced that sodium thiosulfate pentahydrate raw material fora new pharmaceutical product must be manufactured in accordance with“pharmaceutical grade” Good Manufacturing Practices and must conform toa new set of quality specifications. This new set of qualityspecifications is more expansive and stringent than the existing qualityspecifications. Currently available sodium thiosulfate pentahydrate rawmaterial does not meet the new set of FDA quality standards and isunsuitable for use in the formulation of a new pharmaceutical product.Consequently, there is a clear and unmet need for purified sodiumthiosulfate pentahydrate raw material that is manufactured in accordancewith “pharmaceutical grade” Good Manufacturing Practices and that meetsthe new set of quality specifications in order to translate recentsodium thiosulfate pentahydrate-related research discoveries intoFDA-approved clinical therapies.

Another hurdle in developing pharmaceutical grade sodium thiosulfatepentahydrate is the lack of an effective analytical method to determinetotal non-purgeable organic carbon in a sodium thiosulfatepentahydrate-containing sample, which is one of the new FDA-imposedquality standards. The conventional method for total non-purgeableorganic carbon determination requires that any inorganic carbon must beremoved before measuring the organic carbon content in a sample. This istypically achieved by adding acid. At low pH, the inorganic carbon andvolatile organic carbon are converted to carbon dioxide, which is thenpurged from the sample. The sample is then routed to a combustionchamber with a catalyst and a temperature of approximately 680° C. toconvert any remaining non-purgeable (non-volatile) organic carbon tocarbon dioxide. The quantity of carbon dioxide thus produced is thendetermined using an infrared detector. However, this conventional methodcannot be used to analyze a sodium thiosulfate pentahydrate-containingsample. When exposed to acid, sodium thiosulfate pentahydrate degradesto sulfur which can precipitate during the analysis. Salt from sodiumthiosulfate pentahydrate may also precipitate during the analysis.Precipitants can damage laboratory equipment and interfere withanalysis. Therefore, there is also a need for an analytical method fordetermining total non-purgeable organic carbon in a sodium thiosulfatepentahydrate-containing sample.

SUMMARY OF THE DISCLOSURE

Provided herein is sodium thiosulfate which contains no greater thanabout 10 ppm of non-purgeable organic carbon (NPOC) (also known asnon-volatile organic carbon). Also provided herein is sodium thiosulfatewhich contains no greater than about 0.01% by weight of carbonate. Alsoprovided herein is sodium thiosulfate which contains no greater thanabout 0.05 ppm of mercury. Also provided herein is sodium thiosulfatewhich contains no greater than about 0.003% by weight of selenium. Alsoprovided herein is sodium thiosulfate which contains no greater thanabout 2 ppm of aluminum. Further provided herein is sodium thiosulfatewhich contains no greater than about 10 ppm of non-purgeable organiccarbon, no greater than about 0.01% by weight of carbonate, no greaterthan about 0.05 ppm of mercury, no greater than about 0.003% by weightof selenium, and no greater than about 2 ppm of aluminum.

Also provided herein are pharmaceutical compositions, which comprisesodium thiosulfate and a pharmaceutically acceptable excipient, whereinthe sodium thiosulfate contains no greater than about 10 ppm ofnon-purgeable organic carbon and/or no greater than about 0.01% byweight of carbonate and/or no greater than about 0.05 ppm of mercuryand/or no greater than about 0.003% by weight of selenium and/or nogreater than about 2 ppm of aluminum.

Also provided herein are methods of determining the total non-purgeableorganic carbon in a sodium thiosulfate-containing sample, whichcomprises the steps of: a) contacting the sample with a predeterminedamount of an inorganic acid-containing aqueous solution to form anaqueous sample solution; b) removing precipitates from the aqueoussample solution; c) contacting the sample solution with a predeterminedamount of an oxidizer; and d) converting the organic carbon in thesample solution into carbon dioxide under a supercritical wateroxidation (SCWO) condition. In one embodiment, the final amount of theinorganic acid is no less than about 2% of the final volume of thesample solution or the final amount of the oxidizer is no less thanabout 20% of the final volume of the sample solution.

Also provided are methods for preparing the sodium thiosulfate providedherein, which comprise the steps of: a) contacting sodium sulfite withsulfur in a solvent to form a reaction mixture; b) filtering thereaction mixture to yield a solution; c) concentrating the solution; d)exposing the solution to activated carbon; e) filtering the solutionwith activated carbon; and f) crystallizing the sodium thiosulfatepentahydrate from the solution.

Also provided herein are methods for treating an acute poisoning,including, but not limited to, cyanide poisoning, which compriseadministering to a subject having an acute poisoning a therapeuticallyeffective amount of sodium thiosulfate provided herein.

Also provided herein are methods for treating or preventing aplatinum-induced ototoxicity, such as that is associated with the use ofcisplatin or other platinum-containing pharmaceutical agents, whichcomprise administering to a subject having or at risk for having aplatinum-induced ototoxicity, such as that is associated with the use ofcisplatin or other platinum-containing pharmaceutical agents, atherapeutically effective amount of sodium thiosulfate provided herein.

Also provided herein are methods for treating or preventing aplatinum-induced nephrotoxicity, such as that associated with the use ofcisplatin or other platinum-containing pharmaceutical agents, whichcomprise administering to a subject having or at risk for having aplatinum-induced nephrotoxicity, such as that associated with the use ofcisplatin or other platinum-containing pharmaceutical agents, atherapeutically effective amount of sodium thiosulfate provided herein.

Also provided herein are methods for treating a calciphylaxis whichcomprise administering to a subject having a calciphylaxis atherapeutically effective amount of sodium thiosulfate provided herein.

Also provided herein are methods for treating a vascular calcification,including by not limited to atherosclerosis, which compriseadministering to a subject having a vascular calcification, including bynot limited to atherosclerosis, a therapeutically effective amount ofsodium thiosulfate provided herein.

Also provided herein are methods for treating a dermatological diseaseor a condition associated with the skin, including, but not limited to,bacterial infection of the skin, mycotic infection of the skin, viralinfection of the skin, mycotic infection of the nails, bacterialinfection of the nails, viral infection of the nails, mycotic infectionof the nailbeds, bacterial infection of the nailbeds, viral infection ofthe nailbeds, psoriasis, scleroderma, inflammation of the skin,inflammation of the nails, and inflammation of the nailbeds, whichcomprise administering to a subject having a dermatological disease or acondition associated with the skin, a therapeutically effective amountof sodium thiosulfate provided herein.

DETAILED DESCRIPTION

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures ininorganic chemistry, analytical chemistry, organic chemistry, medicinalchemistry, and pharmacology described herein are those well known andcommonly employed in the art. Unless defined otherwise, all technicaland scientific terms used herein generally have the same meaning ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs. In the event that there is a plurality ofdefinitions for a term used herein, those in this section prevail unlessstated otherwise.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat,or mouse. The terms “subject” and “patient” are used interchangeablyherein in reference, for example, to a mammalian subject, such as ahuman subject. In one embodiment, the subject has or is at risk for adisease, disorder or condition provided herein. In another embodiment,the patient has or is at risk for a disease, disorder or conditionwherein the disease, disorder or condition, or a symptom thereof, can betreated, prevented or ameliorated by the administration of sodiumthiosulfate.

The term “host” refers to a unicellular or multicellular organism inwhich a virus can replicate, including, but not limited to, a cell, cellline, and animal, such as human.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder, disease, or condition, or one ormore of the symptoms associated with the disorder, disease, orcondition; or alleviating or eradicating the cause(s) of the disorder,disease, or condition itself.

The terms “prevent,” “preventing,” and “prevention” are meant to includea method of delaying and/or precluding the onset of a disorder, disease,or condition, and/or its attendant symptom(s); barring a subject fromacquiring a disease; or reducing a subject's risk of acquiring adisorder, disease, or condition.

The term “therapeutically effective amount” is meant to include theamount of a compound, such as sodium thiosulfate, that, whenadministered, is sufficient to treat or prevent development of, oralleviate to some extent, one or more of the symptoms of the disorder,disease, or condition being treated. The term “therapeutically effectiveamount” also refers to the amount of a compound, such as sodiumthiosulfate, that is sufficient to elicit the biological or medicalresponse of a cell, tissue, system, animal, or human, which is beingsought by a researcher, veterinarian, medical doctor, or clinician.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid (e.g., water, such as deionized or sterile water) or solidfiller, diluent, excipient, solvent, or encapsulating material. In oneembodiment, each component is “pharmaceutically acceptable” in the senseof being compatible with the other ingredients of a pharmaceuticalformulation, and suitable for use in contact with cells, tissues, ororgans of humans and animals without excessive toxicity, irritation,allergic response, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, Remington: TheScience and Practice of Pharmacy, 21st Edition, Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,5th Edition, Rowe et al., Eds., The Pharmaceutical Press and theAmerican Pharmaceutical Association: 2005; and Handbook ofPharmaceutical Additives, 3rd Edition, Ash and Ash Eds., GowerPublishing Company: 2007; Pharmaceutical Preformulation and Formulation,Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2004.

The term “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of agiven value or range. In certain embodiments, it is contemplated thatthe values preceded by the term “about” or “approximately” are exact.

The terms “active pharmaceutical ingredient”, “active ingredient” and“active substance” refer to a compound, which is administered, alone orin combination with one or more pharmaceutically acceptable excipients,to a subject for treating, preventing, or ameliorating one or moresymptoms of a condition, disorder, or disease. As used herein, “activepharmaceutical ingredient”, “active ingredient” and “active substance”may be an optically active isomer of a compound described herein. Asused herein, “active pharmaceutical ingredient”, “active ingredient”,and “active substance” may be the anhydrous, the monohydrate, dihydrate,trihydrate, quatrahydrate, pentahydrate, or other hydrated forms ofsodium thiosulfate.

The term “sodium thiosulfate” includes anhydrous, monohydrate,dihydrate, trihydrate, quatrahydrate, pentahydrate, and other hydratedforms of sodium thiosulfate. In one embodiment, the “sodium thiosulfate”referred to herein is sodium thiosulfate pentahydrate (Na₂S₂O₃.5H₂O). Inanother embodiment, the sodium thiosulfate is pharmaceutical grade. Theterm “pharmaceutical grade” as used herein with respect to sodiumthiosulfate means that the sodium thiosulfate was manufactured accordingto Good Manufacturing Practices (GMP) as detailed in the United StatesCode of Federal Regulations 21 CFR 211 and meets one or more of thepurity levels recited herein.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent”refer to a compound, or a pharmaceutical composition thereof, which isadministered to a subject for treating, preventing, or ameliorating oneor more symptoms of a condition, disorder, or disease.

The term “anti-solvent” refers to a liquid that is added to a solvent toreduce the solubility of a compound in that solvent, resulting inprecipitation of the compound.

The terms “non-purgeable organic carbon” (“NPOC”) and “non-volatileorganic carbon” (“NVOC”) refer to organic carbon-based substances thatare not volatile and are not purged from material when exposed to acid.

1. Sodium Thiosulfate

Provided herein are purified forms of sodium thiosulfate, such as sodiumthiosulfate pentahydrate (Na₂S₂O₃.5H₂O). In one embodiment, providedherein is pharmaceutical grade sodium thiosulfate. In anotherembodiment, provided herein are forms of sodium thiosulfate meeting orexceeding one, more than one or all FDA standards for sodium thiosulfatefor pharmaceutical use. In another embodiment, provided herein are formsof sodium thiosulfate that were manufactured according to GoodManufacturing Practices (GMP) as detailed in the United States Code ofFederal Regulations 21 CFR 211.

In one embodiment, the sodium thiosulfate is solid.

In one embodiment, the appearance of the sodium thiosulfate is colorlesscrystals.

In one embodiment, the appearance of a 10% solution containing thesodium thiosulfate is clear and colorless.

In one embodiment, the sodium thiosulfate is odorless.

In one embodiment, the presence of sodium thiosulfate in a 10% solutioncontaining sodium thiosulfate provided herein is identified by thedischarge of yellow color after the addition of a few drops of iodineTS.

In one embodiment, the presence of sodium in sodium thiosulfate providedherein is confirmed according to Method 191 in USP XXXII (2009), whichis incorporated by reference herein in its entirety.

In one embodiment, the presence of thiosulfate in sodium thiosulfateprovided herein is confirmed according to Method 191 in USP XXXII(2009).

In one embodiment, the sodium thiosulfate pentahydrate provided hereincontains no less than about 99% by weight and/or no greater than about100.5% by weight of sodium thiosulfate calculated on the anhydrousbasis. In certain embodiments, the amount of anhydrous sodiumthiosulfate in the sodium thiosulfate pentahydrate provided herein isdetermined according to USP colorimetric assay (USP XXXII (2009)).

In one embodiment, the sodium thiosulfate pentahydrate provided hereincontains no less than about 98% by weight and no greater than about 102%by weight of sodium thiosulfate on an anhydrous basis as measured by ionchromatography.

In one embodiment, the sodium thiosulfate pentahydrate provided hereincontains no less than about 98% by weight and/or no greater than about102% by weight of sodium thiosulfate calculated on the anhydrous basis.In certain embodiments, the amount of sodium thiosulfate anhydrous inthe sodium thiosulfate pentahydrate provided herein is determined by anion chromatography. In certain embodiments, the amount of anhydroussodium thiosulfate in the sodium thiosulfate pentahydrate providedherein is determined by an ion chromatography with electrochemicalconductivity detection as described herein.

In another embodiment, the sodium thiosulfate provided herein has a pHbetween about 6 to about 8 when measured in a 10% solution at 25° C. Incertain embodiments, the pH of the sodium provided herein is measuredusing a pH meter. In certain embodiments, the pH of the sodiumthiosulfate provided herein is determined according to Method 791 in USPXXXII (2009).

In yet another embodiment, the sodium thiosulfate provided herein haswater content of about 32% to about 37% by weight. In certainembodiments, the water content in the sodium thiosulfate provided hereinis determined by Karl Fischer method. In certain embodiments, the watercontent in the sodium thiosulfate provided herein is quantitatedaccording to Method 921 in USP XXXII (2009).

In yet another embodiment, the heavy metal content in the sodiumthiosulfate provided herein is no greater than about 10 ppm of a heavymetal. The heavy metal content in the sodium thiosulfate provided hereinis determined according to Method 231 in USP XXXII (2009).

In yet another embodiment, the sodium thiosulfate provided hereincontains no greater than about 0.01% by weight of carbonate. In certainembodiments, the amount of carbonate in the sodium thiosulfate providedherein is determined by contacting a sodium thiosulfate sample with anacid, such as phosphoric acid, to convert carbonate to carbon dioxideand determining the amount of the carbon dioxide using a non-dispersiveinfrared detector.

In yet another embodiment, the sodium thiosulfate provided hereincontains no greater than about 0.005% by weight of insoluble matter. Incertain embodiments, the amount of insoluble material in the sodiumthiosulfate provided herein is determined by dissolving 10 grams of thesodium thiosulfate provided herein in 100 mL of water, the solution isheated to boiling for 1 hr, the solution is filtered, washed with hotwater, dried, cooled in a desiccator, and weighed.

In yet another embodiment, the sodium thiosulfate provided hereincontains no greater than about 200 ppm by weight of chloride. In certainembodiments, the chloride content in the sodium thiosulfate providedherein is determined according to Method 221 in USP XXXII (2009).

In yet another embodiment, the sodium thiosulfate provided hereincontains no greater than about 0.002% by weight of iron. In certainembodiments, the iron content in the sodium thiosulfate provided hereinis determined using inductively coupled plasma mass spectrometry(ICP-MS). In certain embodiments, the iron content in the sodiumthiosulfate provided herein is determined using inductively coupledplasma-optical emission spectroscopy (ICP-OES). In certain embodiments,the iron content in the sodium thiosulfate provided herein is determinedaccording to Method 241 in USP XXXII (2009).

In yet another embodiment, the sodium thiosulfate provided hereincontains no greater than about 0.001% by weight of lead. In certainembodiments, the lead content in the sodium thiosulfate provided hereinis determined according to Method 251 in USP XXXII (2009).

In yet another embodiment, the sodium thiosulfate provided hereincontains no greater than about 0.01% by weight of calcium. In certainembodiments, the calcium content in the sodium thiosulfate providedherein is determined using ICP-MS. In certain embodiments, the calciumcontent in the sodium thiosulfate provided herein is determined usingflame emission spectrometry (FES).

In yet another embodiment, the sodium thiosulfate provided herein causesno turbidity when ammonium oxalate test solution prepared according toUSP XXXII (2009) is added to an aqueous solution containing sodiumthiosulfate (e.g., one gram of sodium thiosulfate dissolved in 20 mL ofwater).

In yet another embodiment, the sodium thiosulfate provided hereincontains no greater than about 0.005% by weight of potassium. In certainembodiments, the potassium content in the sodium thiosulfate providedherein is determined using ICP-MS. In certain embodiments, the potassiumcontent in the sodium thiosulfate provided herein is determined usingFES.

In yet another embodiment, the sodium thiosulfate provided hereincontains no greater than about 0.05% by weight of sulfite, or no greaterthan about 0.1% by weight of sulfite. In certain embodiments, thesulfite content in the sodium thiosulfate provided herein is determinedaccording to the method for the determination of sulfite in AmericanChemical Society, Reagent Chemicals, 10^(th) Edition, incorporated byreference herein in its entirety.

In yet another embodiment, the sodium thiosulfate provided hereincontains no greater than about 0.05%, no greater than about 0.1%, nogreater than about 0.25%, or no greater than about 0.5% by weight ofsulfate (as SO₄). In certain embodiments, the sulfate content in thesodium thiosulfate provided herein is determined according to the methodfor the determination of sulfate in American Chemical Society, ReagentChemicals, 10^(th) Edition.

In yet another embodiment, the sodium thiosulfate provided hereincontains no greater than about 0.001% by weight of sulfide. In certainembodiments, the sulfide content in the sodium thiosulfate providedherein is determined by the addition of lead (II) nitrate using methodsdescribed herein.

In yet another embodiment, the sodium thiosulfate provided hereincontains no greater than about 0.002% by weight of nitrogen compounds(as N). In certain embodiments, the nitrogen compounds (as N) content inthe sodium thiosulfate provided herein is determined according to themethod for the determination of nitrogen compounds in American ChemicalSociety, Reagent Chemicals, 10^(th) Edition.

In yet another embodiment, the sodium thiosulfate provided hereincontains no greater than about 10 ppm, no greater than about 100 ppm, nogreater than about 500 ppm, no greater than about 1000 ppm, or nogreater than 5000 ppm of total volatile organic carbon. In certainembodiments, the sodium thiosulfate provided herein contains no greaterthan the specific limits set forth in ICH Q3C(R3) for organic volatileimpurities or a particular solvent (e.g., ethanol), the disclosure ofwhich is incorporated by references in its entirety. In certainembodiments, the content of organic volatile impurities is determinedaccording to Method 467 in USP XXXII (2009).

In yet another embodiment, the sodium thiosulfate provided hereincontains total NPOC of no greater than about 60 ppb, no greater thanabout 2.5 ppm, no greater than about 8 ppm, no greater than about 10ppm, no greater than about 20 ppm, no greater than about 25 ppm, or nogreater than about 50 ppm. In certain embodiments, the sodiumthiosulfate provided herein contains total NPOC of no greater than about12 ppm. In certain embodiments, the total NPOC in the sodium thiosulfateprovided herein is determined using methods described herein. In certainembodiments, the total NPOC in the sodium thiosulfate provided herein isdetermined by a) contacting the sodium thiosulfate with a predeterminedamount of an inorganic acid-containing aqueous solution to form anaqueous sample solution; b) removing precipitates from the aqueoussample solution; c) contacting the sample solution with a predeterminedamount of an oxidizer; and d) converting the organic carbon in thesample solution into carbon dioxide under a supercritical wateroxidation (SCWO) condition.

In yet another embodiment, the sodium thiosulfate provided hereincontains no greater than about 0.05 ppm of mercury. In certainembodiments, the mercury content in the sodium thiosulfate providedherein is determined using ICP-MS. In certain embodiments, the mercurycontent in the sodium thiosulfate provided herein is determined usingICP-OES. In certain embodiments, the mercury content in the sodiumthiosulfate provided herein is determined according to Method 261 in USPXXXII (2009).

In yet another embodiment, the sodium thiosulfate provided hereincontains no greater than about 2 ppm of aluminum. In certainembodiments, the aluminum content in the sodium thiosulfate providedherein is determined using ICP-MS. In certain embodiments, the aluminumcontent in the sodium thiosulfate provided herein is determined usingICP-OES. In certain embodiments, the aluminum content in the sodiumthiosulfate provided herein is determined according to Method 206 in USPXXXII (2009).

In yet another embodiment, the sodium thiosulfate provided hereincontains no greater than about 3 ppm of arsenic. In certain embodiments,the arsenic content in the sodium thiosulfate provided herein isdetermined using ICP-MS. In certain embodiments, the arsenic content inthe sodium thiosulfate provided herein is determined using ICP-OES. Incertain embodiments, the arsenic content in the sodium thiosulfateprovided herein is determined according to Method 211 in USP XXXII(2009).

In yet another embodiment, the sodium thiosulfate provided hereincontains no greater than about 0.003% by weight of selenium. In certainembodiments, the selenium content in the sodium thiosulfate providedherein is determined using ICP-MS. In certain embodiments, the seleniumcontent in the sodium thiosulfate provided herein is determined usingICP-OES. In certain embodiments, the selenium content in the sodiumthiosulfate provided herein is determined according to Method 291 in USPXXXII (2009).

In yet another embodiment, the total aerobic count of microbial load inthe sodium thiosulfate provided herein is no greater than about 100Colony Forming Units per gram (CFU/g). The total aerobic count ofmicrobial load in the sodium thiosulfate provided herein is quantitatedaccording to Method 61 in USP XXXII (2009).

In yet another embodiment, the total yeast and mold count in the sodiumthiosulfate provided herein is no greater than about 20 CFU/g. The totalyeast and mold count in the sodium thiosulfate provided herein isquantitated according to Method 61 in USP XXXII (2009).

In yet another embodiment, the sodium thiosulfate provided hereincontains no greater than about 0.02 Endotoxin Units per milligram(EU/mg), no greater than about 0.1 EU/mg, or no greater than about 0.25EU/mg of bacterial endotoxins. The amount of bacterial endotoxins in thesodium thiosulfate provided herein is quantitated according to Method 85in USP XXXII (2009).

In yet another embodiment, the sodium thiosulfate provided hereincontains no greater than 0.01% of a residual anti-caking agent.

In yet another embodiment, the sodium thiosulfate provided herein ischaracterized by one or more of the following:

containing no less than about 99% by weight and/or no greater than about100.5% by weight of sodium thiosulfate on an anhydrous basis determinedaccording to USP colormimetric assay;

containing no less than about 98% by weight and/or no greater than about102% by weight of sodium thiosulfate on an anhydrous basis determinedaccording to ion chromatography assay;

having a pH between about 6 to about 8 when measured in a 10% solutionat 25° C.;

having water content of about 32% to about 37% by weight;

having an appearance of colorless crystals;

having a clear and colorless appearance as a 10% solution;

having no odor;

having a positive identification test for sodium;

having a positive identification test for thiosulfate;

having no turbidy when mixed with ammonium oxalate TS;

having heavy metal content of no greater than about 10 ppm;

containing no greater than about 0.01% by weight of carbonate;

containing no greater than about 0.005% by weight of insoluble matter;

containing no greater than about 200 ppm of chloride;

containing no greater than about 0.001% by weight of sulfide;

containing no greater than about 0.05% or no greater than about 0.1% byweight of sulfite;

containing no greater than about 0.05%, no greater than about 0.1%, nogreater than about 0.25%, or no greater than about 0.5% by weight ofsulfate;

containing no greater than about 0.002% by weight of iron;

containing no greater than about 0.01% by weight of calcium;

containing no greater than about 0.005% by weight of potassium;

containing no greater than about 10 ppm, no greater than about 100 ppm,no greater than about 500 ppm, no greater than about 1000 ppm, or nogreater than 5000 ppm of organic volatile impurities;

having total NPOC of no greater than 60 ppb, no greater than about 2.5ppm, no greater than about 8 ppm, no greater than about 10 ppm, nogreater than about 20 ppm, no greater than about 25 ppm, or no greaterthan about 50 ppm;

containing no greater than about 0.05 ppm of mercury;

containing no greater than about 2 ppm of aluminum;

containing no greater than about 3 ppm of arsenic;

containing no greater than 0.001% by weight of lead;

containing no greater than about 0.002% by weight of nitrogen compounds(as N);

containing no greater than about 0.003% by weight of selenium;

containing no greater than 0.01% of a residual anti-caking agent;

having a total aerobic count of microbial load of no greater than about100 CFU/g;

having a total yeast and mold count of no greater than about 20 CFU/g;and

containing no greater than about 0.02 EU/mg, no greater than about 0.1EU/mg, or no greater than about 0.25 EU/mg of bacterial endotoxins.

In still another embodiment, the sodium thiosulfate provided herein ischaracterized by one or more of the following:

containing no less than about 99% by weight and/or no greater than about100.5% by weight of sodium thiosulfate on an anhydrous basis determinedaccording to USP colormimetric assay;

containing no less than about 98% by weight and/or no greater than about102% by weight of sodium thiosulfate on an anhydrous basis determinedaccording to ion chromatography assay;

having a pH between about 6 to about 8 when measured in a 10% solutionat 25° C.;

having water content of about 32% to about 37% by weight;

having an appearance of colorless crystals;

having a clear and colorless appearance as a 10% solution;

having no odor;

having a positive identification test for sodium;

having a positive identification test for thiosulfate;

having no turbidy when mixed with ammonium oxalate TS;

having heavy metal content of no greater than about 10 ppm;

containing no greater than about 0.01% by weight of carbonate;

containing no greater than about 0.005% by weight of insoluble matter;

containing no greater than about 200 ppm of chloride;

containing no greater than about 0.001% by weight of sulfide;

containing no greater than about 0.05% or no greater than about 0.1% byweight of sulfite;

containing no greater than about 0.05%, no greater than about 0.1%, nogreater than about 0.25%, or no greater than about 0.5% by weight ofsulfate;

containing no greater than about 0.002% by weight of iron;

containing no greater than about 0.01% by weight of calcium;

containing no greater than about 0.005% by weight of potassium;

containing no greater than about 10 ppm, no greater than about 100 ppm,no greater than about 500 ppm, no greater than about 1000 ppm, or nogreater than 5000 ppm of organic volatile impurities;

having total NPOC of no greater than 60 ppb, no greater than about 2.5ppm, no greater than about 8 ppm, no greater than about 10 ppm, nogreater than about 20 ppm, no greater than about 25 ppm, or no greaterthan about 50 ppm;

containing no greater than about 0.05 ppm of mercury;

containing no greater than about 2 ppm of aluminum;

containing no greater than about 3 ppm of arsenic;

containing no greater than 0.001% by weight of lead;

containing no greater than about 0.002% by weight of nitrogen compounds(as N);

containing no greater than about 0.003% by weight of selenium;

having a total aerobic count of microbial load of no greater than about100 CFU/g;

having a total yeast and mold count of no greater than about 20 CFU/g;and

containing no greater than about 0.02 EU/mg, no greater than about 0.1EU/mg, or no greater than about 0.25 EU/mg of bacterial endotoxins.

In certain embodiments, where the sodium thiosulfate is described as“containing no greater than” a certain amount of a particular material,the sodium thiosulfate does not contain a detectable amount of thematerial.

2. Preparation of Sodium Thiosulfate

In one embodiment, provided herein is a method for preparing the sodiumthiosulfate provided herein, which comprise the steps of: a) contactingsodium sulfite with sulfur in a solvent to form a reaction mixture; b)filtering the reaction mixture to yield a solution; c) concentrating thesolution; d) exposing the solution to activated carbon; e) filtering thesolution with activated carbon; and f) crystallizing the sodiumthiosulfate from the solution.

Suitable solvents for use in the methods provided herein include, butare not limited to, water (including, but not limited to water, purifiedwater, ultrapure water, deionized water, and water for injection),methanol, ethanol, isopropanol (IPA), 1-propanol, 2-methoxyethanol,2-ethoxyethanol, ethyleneglycol, acetone, N,N-dimethylformamide (DMF),N,N-dimethylacetamide, acetonitrile (ACN), dimethyl sulfoxide (DMSO),N-methylpyrrolidone, tetrahydrofuran (THF), dioxane, acetic acid,trichloroacetic acid, trifluoroacetic acid, and a mixture thereof. Inone embodiment, the solvent is aqueous. In another embodiment, thesolvent is water. In yet another embodiment, the solvent is a mixture ofwater with a water-miscible solvent, including, but not limited to,methanol, ethanol, isopropanol (IPA), 1-propanol, 2-methoxyethanol,2-ethoxyethanol, ethyleneglycol, acetone, N,N-dimethylformamide (DMF),N,N-dimethylacetamide, acetonitrile (ACN), dimethyl sulfoxide (DMSO),N-methyl pyrrolidone, tetrahydrofuran (THF), dioxane, acetic acid,trichloroacetic acid, trifluoroacetic acid, and a mixture thereof. Inone embodiment, the solvent is water.

In certain embodiments, the mole ratio of the sulfur to the sodiumsulfite in the contacting step is from about 0.5 to about 5, from about1 to about 4, from about 1 to about 3, from about 1 to about 2, or fromabout 1.2 to about 1.6. In one embodiment, the ratio of the sulfur tothe sodium sulfite in the contacting step is about 1.5.

In certain embodiments, the concentration of the sodium sulfite in thecontacting step is from about 0.1 to about 100 M, from about 1 to about10 M, from about 1 to about 5 M, from about 1 to about 4 M, from about 1to about 3 M, from about 1 to about 2 M, from about 1.2 to about 1.8 M,or from about 1.3 to about 1.6 M. In certain embodiments, theconcentration of the sodium sulfite in the contacting step is from about1.3 to about 1.5 M.

In certain embodiments, the contacting step is carried out at atemperature ranging from about 40 to about 150° C., from about 70 toabout 120° C., from about 90 to about 110° C., from about 90 to about10° C., or from about 95 to about 100° C. In one embodiment, thetemperature in the contacting step is from about 90 to about 100° C. Inanother embodiment, the temperature in the contacting step is from about95 to about 100° C. In still another embodiment, the temperature in thecontacting step is about 97° C.

In certain embodiments, the contacting step is carried out at apredetermined pH of no less than 13, no less than 12, no less than 11,no less than 10, no less than 9, no less than 8, or no less than 7. Incertain embodiments, the predetermined pH is from about 6 to about 11,from about 6.5 to about 10.5, from about 7 to about 10, from about 7 toabout 9, from about 7 to about 8.5, or from about 7 to about 8. Incertain embodiments, a base is added to the reaction mixture in thecontacting step to adjust to the predetermined pH. In certainembodiments, the base is an inorganic base. In certain embodiments, thebase is sodium hydroxide.

In certain embodiments, a filtration step is carried out at atemperature ranging from about 5 to 100° C., from about 10 to about 50°C., from about 15 to about 40° C., from about 20 to about 30° C., orfrom about 20 to about 35° C. In certain embodiments, the filtrationstep is carried out at room temperature (about 21° C.).

In certain embodiments, a concentration step is performed by solventevaporation, which comprises concentrating the filtered solution toproduce a concentrated solution. In certain embodiments, the filteredsolution is concentrated to a specific gravity ranging from about 1.20to about 1.70, from about 1.30 to about 1.60, or from about 1.40 toabout 1.50, or from about 1.40 to about 1.45. In certain embodiments,the concentration step is performed at a temperature ranging from about5 to 100° C., from about 20 to about 80° C., from about 30 to about 70°C., from about 40 to about 60° C., or from about 45 to about 55. Incertain embodiments, the concentration step is performed at about 50° C.In certain embodiments, the concentration step is performed undervacuum. In certain embodiments, the concentration step is performed fromabout 100 to about 755 mm Hg, from 300 to about 750 mm Hg, from 500 toabout 750 mm Hg, from 600 to about 740 mm Hg, or from 700 to about 730mm Hg. In certain embodiments, the concentration step is performed from700 to about 730 mm Hg.

In certain embodiments, the concentrated solution is mixed withactivated carbon of about 0.020 to 0.251% on a weight/weight basis forabout 30 to 47 minutes at about 50° C. In certain embodiments, theactivated carbon step is performed with not less than 0.025% activatedcarbon on a weight/weight basis for not less than 30 minutes at about50° C.

In certain embodiments, the solution with activated carbon is refilteredat a temperature from about 20 to 55° C., or from about 40 to about 55°C. In certain embodiments, the refiltration step is performed at about50° C.

In certain embodiment, the sodium thiosulfate pentahydrate iscrystallized out from the concentrated, refiltered solution usingconventional methods, including, but not limited to, cooling, chilling,solvent evaporation, addition of an anti-solvent, or reverse addition toan anti-solvent.

To accelerate the crystallization, the crystallization step may furthercomprise the step of seeding the filtered solution. The crystallizationstep may also comprise an isolation step, in which the precipitate maybe isolated by a conventional method, such as filtration andcentrifugation, followed by washing with a solvent and then drying.

Other methods known in the art may also be applicable for preparing thepharmaceutically acceptable sodium thiosulfate provided herein,including spray drying, roller drying, lyophilization, and meltcrystallization.

3. Methods of Characterization: Determining the Total Non-PurgeableOrganic Carbon in Sodium Thiosulfate

Provided herein are methods of determining the total non-purgeableorganic carbon in a sodium thiosulfate-containing sample, which comprisethe steps of: a) contacting the sample with a predetermined amount of aninorganic acid-containing aqueous solution to form an aqueous samplesolution; b) removing precipitates from the aqueous sample solution; c)contacting the sample solution with a predetermined amount of anoxidizer; and d) converting the organic carbon in the sample solutioninto carbon dioxide under a supercritical water oxidation (SCWO)condition. In one embodiment, the final amount of the inorganic acid isno less than about 2% of the final volume of the sample solution or thefinal amount of the oxidizer is no less than about 20% of the finalvolume of the sample solution.

In one embodiment, the inorganic acid is phosphoric acid. In anotherembodiment, the inorganic acid is 6 N phosphoric acid. In yet anotherembodiment, the final amount of the inorganic acid is no less than about2% and no greater than about 50% of the final volume of the samplesolution. In yet another embodiment, the final amount of the inorganicacid is about 2%, about 3%, about 4%, about 5%, about 6%, about 7%,about 8%, about 9%, about 10%, about 15%, about 20%, about 30%, about40%, or about 50% of the final volume of the sample solution. In yetanother embodiment, the final amount of the inorganic acid is about 6%of the final volume of the sample solution. In still another embodiment,the inorganic acid is 6 N phosphoric acid and the final amount of theinorganic acid is about 6% of the final volume of the sample solution.

The precipitates in the aqueous sample solution, if any, can be readilyremoved from the sample solution by methods known to one of skill in theart. In certain embodiments, the precipitates are removed from thesample solution by filtration. In certain embodiments, the precipitatesare removed from the sample solution by centrifugation.

In one embodiment, the oxidizer is sodium persulfate. In anotherembodiment, the oxidizer is a 30% sodium persulfate solution. In yetanother embodiment, the final amount of the oxidizer is no less thanabout 20% but no greater than about 90% of the final volume of thesample solution. In yet another embodiment, the final amount of theoxidizer is about 20%, about 25%, about 30%, about 35%, about 40%, about45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, or about 90% of the final volume of the sample solution. Inyet another embodiment, the final amount of the oxidizer is about 45% ofthe final volume of the sample solution. In still another embodiment,the oxidizer is 30% sodium persulfate solution and the final amount ofoxidizer is about 45% of the final volume of the sample solution.

In certain embodiments, the organic carbon in the sodiumthiosulfate-containing sample is oxidized according any SCWO processesknown in the art, such as those disclosed in U.S. Pat. Nos. 2,944,396,4,543,190, 5,387,398, 5,405,533, 5,501,799, 5,560,822, 5,804,066,6,054,057, 6,056,883, 6,238,568, 6,519,926, 6,576,185, 6,709,602, and6,773,581, the disclosure of each of which is incorporated herein byreference in its entirety. In certain embodiments, the SCWO process iscarried out in an InnovOx laboratory TOC Analyzer (GE AnalyticalInstruments, Inc., Boulder, Colo.). SCWO processes take advantage of theunique properties of water at conditions near and beyond thethermodynamic critical point of water (i.e., 375° C. and 218 atm). Theincreased pressure under supercritical water oxidation conditionsdramatically increases the efficiency of the oxidation process byconverting the organic carbon in the sodium thiosulfate-containingsample into carbon dioxide.

In certain embodiments, the sodium thiosulfate-containing samplesolution is prepared by adding 5.0 g of a sodium thiosulfate-containingsample into water to make 100 mL solution. In certain embodiments, thewater used in the method has total organic carbon of no greater than0.10 ppm.

In certain embodiments, the method further comprises the step ofdetermining the amount of carbon dioxide formed after oxidation. Incertain embodiments, the carbon dioxide is quantitated using an infrareddetector. In certain embodiments, the carbon dioxide is quantitatedusing a nondispersive infrared detector.

4. Pharmaceutical Compositions

Provided herein are pharmaceutical compositions comprising the sodiumthiosulfate provided herein as an active ingredient, alone or incombination with a pharmaceutically acceptable vehicle, carrier,diluent, or excipient, or a mixture thereof.

The sodium thiosulfate provided herein may be administered alone, or incombination with one or more other active ingredients. Thepharmaceutical compositions that comprise the sodium thiosulfateprovided herein may be formulated in various dosage forms for oral,parenteral, and topical administration. The pharmaceutical compositionsmay also be formulated as modified release dosage forms, includingdelayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-,accelerated- and fast-, targeted-, programmed-release, and gastricretention dosage forms. These dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra;Modified-Release Drug Deliver Technology, Rathbone et al., Eds., Drugsand the Pharmaceutical Science, Marcel Dekker, Inc.: New York, N.Y.,2003; Vol. 126).

In one embodiment, the pharmaceutical compositions are provided in adosage form for oral administration, which comprise the sodiumthiosulfate provided herein, and one or more pharmaceutically acceptableexcipients or carriers.

In another embodiment, the pharmaceutical compositions are provided in adosage form for parenteral administration, which comprise the sodiumthiosulfate provided herein, and one or more pharmaceutically acceptableexcipients or carriers.

In yet another embodiment, the pharmaceutical compositions are providedin a dosage form for topical administration, including pulmonaryadministration, which comprise the sodium thiosulfate provided herein,and one or more pharmaceutically acceptable excipients or carriers.

In one embodiment, the pharmaceutical composition comprises sodiumthiosulfate provided herein and water. In another embodiment, thepharmaceutical composition comprises from about 1 gram to about 100grams, about 1 gram to about 75 grams, about 1 gram to about 50 grams,about 1 gram to about 25 grams or about 1 gram to about 12.5 grams ofsodium thiosulfate provided herein in about 1 mL to about 1000 mL, about1 mL to about 750 mL, about 1 mL to about 500 mL, about 1 mL to about250 mL about 1 mL to about 100 mL, about 1 mL to about 50 mL or about 1mL to about 25 mL of water. In another embodiment, the pharmaceuticalcomposition comprises about 5 grams, about 10 grams, about 12.5 grams,about 15 grams, about 20 grams, about 25 grams, about 30 grams, about 50grams, about 75 grams or about 100 grams or more of sodium thiosulfateprovided herein in about 25 mL, about 50 mL, about 100 mL, about 250 mL,about 500 mL, about 750 mL or about 1000 mL or more of water.

In one embodiment, the pharmaceutical composition comprises sodiumthiosulfate provided herein, one or more isotonic agents and one or morepH adjusting agents. In another embodiment, the pharmaceuticalcomposition comprises sodium thiosulfate provided herein, one or moreisotonic agents, one or more buffering agents and one or more pHadjusting agents. In a particular embodiment, the pharmaceuticalcomposition comprises sodium thiosulfate provided herein, potassiumchloride, boric acid and sodium hydroxide. In a specific embodiment, thepharmaceutical composition comprises sodium thiosulfate provided herein,potassium chloride, boric acid, sodium hydroxide and water (e.g., waterfor injection).

In one embodiment, the pharmaceutical composition comprises sodiumthiosulfate provided herein and salicylic acid. In another embodiment,the pharmaceutical composition comprises about 5 to about 50%, about 10to about 40%, about 15 to about 30% or about 20 to about 25% of sodiumthiosulfate provided herein and about 0.1 to about 2%, about 0.1 toabout 1.5%, about 0.5 to about 1.5%, about 0.5 to about 1.25% or about0.5 to about 1% salicylic acid in a lotion. In another embodiment, thepharmaceutical composition comprises about 10%, about 15%, about 20%,about 25%, about 30% about 35% or about 40% or more of sodiumthiosulfate provided herein and about 0.5%, about 0.75%, about 1%, about1.25%, about 1.5% or about 2% salicylic acid in a lotion.

The pharmaceutical compositions provided herein may be provided in aunit-dosage form or multiple-dosage form. A unit-dosage form, as usedherein, refers to a physically discrete unit suitable for administrationto a human and animal subject, and packaged individually as is known inthe art. Each unit-dose contains a predetermined quantity of the activeingredient(s) sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carriers or excipients.Examples of a unit-dosage form include an ampoule, syringe, andindividually packaged tablet or capsule. A unit-dosage form may beadministered in fractions or multiples thereof. A multiple-dosage formis a plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dosage form. Examples ofa multiple-dosage form include a vial, bottle of tablets or capsules, orbottle of pints or gallons.

The pharmaceutical compositions provided herein may be administered atonce, or multiple times at intervals of time. It is understood that theprecise dosage and duration of treatment may vary with the age, weight,and condition of the patient being treated, and may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test or diagnostic data. It is further understood thatfor any particular individual, specific dosage regimens should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the formulations.

4.1. Oral Administration

The pharmaceutical compositions provided herein may be provided insolid, semisolid, or liquid dosage forms for oral administration. Asused herein, oral administration also includes buccal, lingual, andsublingual administration. Suitable oral dosage forms include, but arenot limited to, tablets, capsules, pills, troches, lozenges, pastilles,cachets, pellets, medicated chewing gum, granules, bulk powders,effervescent or non-effervescent powders or granules, solutions,emulsions, suspensions, solutions, wafers, sprinkles, elixirs, andsyrups. In addition to the active ingredient(s), the pharmaceuticalcompositions may contain one or more pharmaceutically acceptablecarriers or excipients, including, but not limited to, binders, fillers,diluents, disintegrants, wetting agents, lubricants, glidants, coloringagents, dye-migration inhibitors, sweetening agents, and flavoringagents.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. The binder or filler may be present fromabout 50 to about 99% by weight in the pharmaceutical compositionsprovided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of a disintegrant in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The pharmaceutical compositions provided herein may containfrom about 0.5 to about 15% or from about 1 to about 5% by weight of adisintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. The pharmaceutical compositionsprovided herein may contain about 0.1 to about 5% by weight of alubricant.

Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (CabotCo. of Boston, Mass.), and asbestos-free talc. Coloring agents includeany of the approved, certified, water soluble FD&C dyes, and waterinsoluble FD&C dyes suspended on alumina hydrate, and color lakes andmixtures thereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Flavoring agents include natural flavorsextracted from plants, such as fruits, and synthetic blends of compoundswhich produce a pleasant taste sensation, such as peppermint and methylsalicylate. Sweetening agents include sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include gelatin, acacia,tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitanmonooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN®80), and triethanolamine oleate. Suspending and dispersing agentsinclude sodium carboxymethylcellulose, pectin, tragacanth, Veegum,acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrrolidone. Preservatives include glycerin, methyl andpropylparaben, benzoic add, sodium benzoate and alcohol. Wetting agentsinclude propylene glycol monostearate, sorbitan monooleate, diethyleneglycol monolaurate, and polyoxyethylene lauryl ether. Solvents includeglycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueousliquids utilized in emulsions include mineral oil and cottonseed oil.Organic acids include citric and tartaric acid. Sources of carbondioxide include sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serveseveral functions, even within the same formulation.

The pharmaceutical compositions provided herein may be provided ascompressed tablets, tablet triturates, chewable lozenges, rapidlydissolving tablets, multiple compressed tablets, or enteric-coatingtablets, sugar-coated, or film-coated tablets. Enteric-coated tabletsare compressed tablets coated with substances that resist the action ofstomach acid but dissolve or disintegrate in the intestine, thusprotecting the active ingredients from the acidic environment of thestomach. Enteric-coatings include, but are not limited to, fatty acids,fats, phenyl salicylate, waxes, shellac, ammoniated shellac, andcellulose acetate phthalates. Sugar-coated tablets are compressedtablets surrounded by a sugar coating, which may be beneficial incovering up objectionable tastes or odors and in protecting the tabletsfrom oxidation. Film-coated tablets are compressed tablets that arecovered with a thin layer or film of a water-soluble material. Filmcoatings include, but are not limited to, hydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol 4000, and cellulose acetatephthalate. Film coating imparts the same general characteristics assugar coating. Multiple compressed tablets are compressed tablets madeby more than one compression cycle, including layered tablets, andpress-coated or dry-coated tablets.

The tablet dosage forms may be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein may be provided as softor hard capsules, which can be made from gelatin, methylcellulose,starch, or calcium alginate. The hard gelatin capsule, also known as thedry-filled capsule (DFC), consists of two sections, one slipping overthe other, thus completely enclosing the active ingredient. The softelastic capsule (SEC) is a soft, globular shell, such as a gelatinshell, which is plasticized by the addition of glycerin, sorbitol, or asimilar polyol. The soft gelatin shells may contain a preservative toprevent the growth of microorganisms. Suitable preservatives are thoseas described herein, including methyl- and propyl-parabens, and sorbicacid. The liquid, semisolid, and solid dosage forms provided herein maybe encapsulated in a capsule. Suitable liquid and semisolid dosage formsinclude solutions and suspensions in propylene carbonate, vegetableoils, or triglycerides. Capsules containing such solutions can beprepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and4,410,545. The capsules may also be coated as known by those of skill inthe art in order to modify or sustain dissolution of the activeingredient.

The pharmaceutical compositions provided herein may be provided inliquid and semisolid dosage forms, including emulsions, solutions,suspensions, elixirs, and syrups. An emulsion is a two-phase system, inwhich one liquid is dispersed in the form of small globules throughoutanother liquid, which can be oil-in-water or water-in-oil. Emulsions mayinclude a pharmaceutically acceptable non-aqueous liquid or solvent,emulsifying agent, and preservative. Suspensions may include apharmaceutically acceptable suspending agent and preservative. Aqueousalcoholic solutions may include a pharmaceutically acceptable acetal,such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g.,acetaldehyde diethyl acetal; and a water-miscible solvent having one ormore hydroxyl groups, such as propylene glycol and ethanol. Elixirs areclear, sweetened, and hydroalcoholic solutions. Syrups are concentratedaqueous solutions of a sugar, for example, sucrose, and may also containa preservative. For a liquid dosage form, for example, a solution in apolyethylene glycol may be diluted with a sufficient quantity of apharmaceutically acceptable liquid carrier, e.g., water, to be measuredconveniently for administration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations may further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administrationmay be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein may be provided asnon-effervescent or effervescent, granules and powders, to bereconstituted into a liquid dosage form. Pharmaceutically acceptablecarriers and excipients used in the non-effervescent granules or powdersmay include diluents, sweeteners, and wetting agents. Pharmaceuticallyacceptable carriers and excipients used in the effervescent granules orpowders may include organic acids and a source of carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical compositions provided herein may be formulated asimmediate or modified release dosage forms, including delayed-,sustained, pulsed-, controlled, targeted-, and programmed-release forms.

The pharmaceutical compositions provided herein may be co-formulatedwith other active ingredients which do not impair the desiredtherapeutic action, or with substances that supplement the desiredaction.

4.2. Parenteral Administration

The pharmaceutical compositions provided herein may be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, intravesical, and subcutaneousadministration.

The pharmaceutical compositions provided herein may be formulated in anydosage forms that are suitable for parenteral administration, includingsolutions, suspensions, emulsions, micelles, liposomes, microspheres,nanosystems, and solid forms suitable for solutions or suspensions inliquid prior to injection. Such dosage forms can be prepared accordingto conventional methods known to those skilled in the art ofpharmaceutical science (see, Remington: The Science and Practice ofPharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationmay include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents (e.g., including, but not limitedto, potassium chloride, mannitol, sodium chloride, dextran and glucose),buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, cryoprotectants, lyoprotectants,thickening agents, pH adjusting agents (e.g., including, but not limitedto, an acid, such as boric acid or a base, such as sodium hydroxide),and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Non-aqueous vehicles include, but are not limited to, fixed oils ofvegetable origin, castor oil, corn oil, cottonseed oil, olive oil,peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Water-miscible vehiclesinclude, but are not limited to, ethanol, 1,3-butanediol, liquidpolyethylene glycol (e.g., polyethylene glycol 300 and polyethyleneglycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone,N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsinclude those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, andsulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

The pharmaceutical compositions provided herein may be formulated forsingle or multiple dosage administration. The single dosage formulationsare packaged in an ampoule, a vial, or a syringe. The multiple dosageparenteral formulations must contain an antimicrobial agent atbacteriostatic or fungistatic concentrations. All parenteralformulations must be sterile, as known and practiced in the art.

In one embodiment, the pharmaceutical compositions are provided asready-to-use sterile solutions. In another embodiment, thepharmaceutical compositions are provided as sterile dry solubleproducts, including lyophilized powders and hypodermic tablets, to bereconstituted with a vehicle prior to use. In yet another embodiment,the pharmaceutical compositions are provided as ready-to-use sterilesuspensions. In yet another embodiment, the pharmaceutical compositionsare provided as sterile dry insoluble products to be reconstituted witha vehicle prior to use. In still another embodiment, the pharmaceuticalcompositions are provided as ready-to-use sterile emulsions.

The pharmaceutical compositions provided herein may be formulated asimmediate or modified release dosage forms, including delayed-,sustained, pulsed-, controlled, targeted-, and programmed-release forms.

The pharmaceutical compositions may be formulated as a suspension,solid, semi-solid, or thixotropic liquid, for administration as animplanted depot. In one embodiment, the pharmaceutical compositionsprovided herein are dispersed in a solid inner matrix, which issurrounded by an outer polymeric membrane that is insoluble in bodyfluids but allows the active ingredient in the pharmaceuticalcompositions to diffuse through.

Suitable inner matrixes include polymethylmethacrylate,polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethylene terephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinyl acetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers, such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinyl alcohol, and cross-linked partiallyhydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinyl chloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer.

4.3. Topical Administration

The pharmaceutical compositions provided herein may be administeredtopically to the skin, orifices, or mucosa. The topical administration,as used herein, includes (intra)dermal, conjunctival, intracorneal,intraocular, ophthalmic, auricular, transdermal, nasal, vaginal,urethral, respiratory, and rectal administration.

The pharmaceutical compositions provided herein may be formulated in anydosage forms that are suitable for topical administration for local orsystemic effect, including emulsions, solutions, suspensions, creams,gels, hydrogels, ointments, dusting powders, dressings, elixirs,lotions, suspensions, tinctures, pastes, foams, films, aerosols,irrigations, sprays, suppositories, bandages, dermal patches. Thetopical formulation of the pharmaceutical compositions provided hereinmay also comprise liposomes, micelles, microspheres, nanosystems, andmixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations provided herein include, but are not limitedto, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryoprotectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical compositions may also be administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis, ormicroneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp.,Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc.,Tualatin, Oreg.).

The pharmaceutical compositions provided herein may be provided in theforms of ointments, creams, and gels. Suitable ointment vehicles includeoleaginous or hydrocarbon vehicles, including lard, benzoinated lard,olive oil, cottonseed oil, and other oils, white petrolatum;emulsifiable or absorption vehicles, such as hydrophilic petrolatum,hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles,such as hydrophilic ointment; water-soluble ointment vehicles, includingpolyethylene glycols of varying molecular weight; emulsion vehicles,either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions,including cetyl alcohol, glyceryl monostearate, lanolin, and stearicacid (see, Remington: The Science and Practice of Pharmacy, supra).These vehicles are emollient but generally require addition ofantioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Cream vehiclesmay be water-washable, and contain an oil phase, an emulsifier, and anaqueous phase. The oil phase is also called the “internal” phase, whichis generally comprised of petrolatum and a fatty alcohol such as cetylor stearyl alcohol. The aqueous phase usually, although not necessarily,exceeds the oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation may be a nonionic, anionic, cationic,or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe liquid carrier. Suitable gelling agents include crosslinked acrylicacid polymers, such as carbomers, carboxypolyalkylenes, CARBOPOL®;hydrophilic polymers, such as polyethylene oxides,polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol;cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, and methylcellulose; gums, such as tragacanth and xanthangum; sodium alginate; and gelatin. In order to prepare a uniform gel,dispersing agents such as alcohol or glycerin can be added, or thegelling agent can be dispersed by trituration, mechanical mixing, and/orstirring.

The pharmaceutical compositions provided herein may be administeredrectally, urethrally, vaginally, or perivaginally in the forms ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses as described in Remington: The Science and Practice ofPharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include bases or vehicles,such as stiffening agents, which produce a melting point in theproximity of body temperature, when formulated with the pharmaceuticalcompositions provided herein; and antioxidants as described herein,including bisulfite and sodium metabisulfite. Suitable vehicles include,but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin,carbowax (polyoxyethylene glycol), spermaceti, paraffin, white andyellow wax, and appropriate mixtures of mono-, di- and triglycerides offatty acids, hydrogels, such as polyvinyl alcohol, hydroxyethylmethacrylate, polyacrylic acid; glycerinated gelatin. Combinations ofthe various vehicles may be used. Rectal and vaginal suppositories maybe prepared by the compressed method or molding. The typical weight of arectal and vaginal suppository is about 2 to about 3 g.

The pharmaceutical compositions provided herein may be administeredophthalmically in the forms of solutions, suspensions, ointments,emulsions, gel-forming solutions, powders for solutions, gels, ocularinserts, and implants.

The pharmaceutical compositions provided herein may be administeredintranasally or by inhalation to the respiratory tract. Thepharmaceutical compositions may be provided in the form of an aerosol orsolution for delivery using a pressurized container, pump, spray,atomizer, such as an atomizer using electrohydrodynamics to produce afine mist, or nebulizer, alone or in combination with a suitablepropellant, such as 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions mayalso be provided as a dry powder for insufflation, alone or incombination with an inert carrier such as lactose or phospholipids; andnasal drops. For intranasal use, the powder may comprise a bioadhesiveagent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer may be formulated to contain ethanol,aqueous ethanol, or a suitable alternative agent for dispersing,solubilizing, or extending release of the active ingredient providedherein, a propellant as solvent; and/or a surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

The pharmaceutical compositions provided herein may be micronized to asize suitable for delivery by inhalation, such as about 50 micrometersor less, or about 10 micrometers or less. Particles of such sizes may beprepared using a comminuting method known to those skilled in the art,such as spiral jet milling, fluid bed jet milling, supercritical fluidprocessing to form nanoparticles, high pressure homogenization, or spraydrying.

Capsules, blisters and cartridges for use in an inhaler or insufflatormay be formulated to contain a powder mix of the pharmaceuticalcompositions provided herein; a suitable powder base, such as lactose orstarch; and a performance modifier, such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate. Other suitable excipients or carriers include dextran,glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.The pharmaceutical compositions provided herein for inhaled/intranasaladministration may further comprise a suitable flavor, such as mentholand levomenthol, or sweeteners, such as saccharin or saccharin sodium.

The pharmaceutical compositions provided herein for topicaladministration may be formulated to be immediate release or modifiedrelease, including delayed-, sustained-, pulsed-, controlled-, targeted,and programmed release.

4.4. Modified Release

The pharmaceutical compositions provided herein may be formulated as amodified release dosage form. As used herein, the term “modifiedrelease” refers to a dosage form in which the rate or place of releaseof the active ingredient(s) is different from that of an immediatedosage form when administered by the same route. Modified release dosageforms include delayed-, extended-, prolonged-, sustained-, pulsatile-,controlled-, accelerated- and fast-, targeted-, programmed-release, andgastric retention dosage forms. The pharmaceutical compositions inmodified release dosage forms can be prepared using a variety ofmodified release devices and methods known to those skilled in the art,including, but not limited to, matrix controlled release devices,osmotic controlled release devices, multiparticulate controlled releasedevices, ion-exchange resins, enteric coatings, multilayered coatings,microspheres, liposomes, and combinations thereof. The release rate ofthe active ingredient(s) can also be modified by varying the particlesizes and polymorphorism of the active ingredient(s).

Examples of modified release include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324;6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461;6,419,961; 6,589,548; 6,613,358; and 6,699,500.

4.4.1. Matrix Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form may be fabricated using a matrix controlled release deviceknown to those skilled in the art (see, Takada et al in “Encyclopedia ofControlled Drug Delivery,” Vol. 2, Mathiowitz Ed., Wiley, 1999).

In one embodiment, the pharmaceutical compositions provided herein in amodified release dosage form is formulated using an erodible matrixdevice, which is water-swellable, erodible, or soluble polymers,including synthetic polymers, and naturally occurring polymers andderivatives, such as polysaccharides and proteins.

Materials useful in forming an erodible matrix include, but are notlimited to, chitin, chitosan, dextran, and pullulan; gum agar, gumarabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gumghatti, guar gum, xanthan gum, and scleroglucan; starches, such asdextrin and maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; and cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethylhydroxy ethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acidesters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acidor methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, N.J.);poly(2-hydroxyethyl-methacrylate); polylactides; copolymers ofL-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolicacid copolymers; poly-D-(−)-3-hydroxybutyric acid; and other acrylicacid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methylmethacrylate, ethylmethacrylate, ethylacrylate,(2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In further embodiments, the pharmaceutical compositions are formulatedwith a non-erodible matrix device. The active ingredient(s) is dissolvedor dispersed in an inert matrix and is released primarily by diffusionthrough the inert matrix once administered. Materials suitable for useas a non-erodible matrix device included, but are not limited to,insoluble plastics, such as polyethylene, polypropylene, polyisoprene,polyisobutylene, polybutadiene, polymethylmethacrylate,polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride,methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetatecopolymers, ethylene/propylene copolymers, ethylene/ethyl acrylatecopolymers, vinyl chloride copolymers with vinyl acetate, vinylidenechloride, ethylene and propylene, ionomer polyethylene terephthalate,butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethylene terephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, silicone carbonate copolymers, andhydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate,and fatty compounds, such as carnauba wax, microcrystalline wax, andtriglycerides.

In a matrix controlled release system, the desired release kinetics canbe controlled, for example, via the polymer type employed, the polymerviscosity, the particle sizes of the polymer and/or the activeingredient(s), the ratio of the active ingredient(s) versus the polymer,and other excipients or carriers in the compositions.

The pharmaceutical compositions provided herein in a modified releasedosage form may be prepared by methods known to those skilled in theart, including direct compression, dry or wet granulation followed bycompression, melt-granulation followed by compression.

4.4.2. Osmotic Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form may be fabricated using an osmotic controlled releasedevice, including one-chamber system, two-chamber system, asymmetricmembrane technology (AMT), and extruding core system (ECS). In general,such devices have at least two components: (a) the core which containsthe active ingredient(s); and (b) a semipermeable membrane with at leastone delivery port, which encapsulates the core. The semipermeablemembrane controls the influx of water to the core from an aqueousenvironment of use so as to cause drug release by extrusion through thedelivery port(s).

In addition to the active ingredient(s), the core of the osmotic deviceoptionally includes an osmotic agent, which creates a driving force fortransport of water from the environment of use into the core of thedevice. One class of osmotic agents water-swellable hydrophilicpolymers, which are also referred to as “osmopolymers” and “hydrogels,”including, but not limited to, hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable ofimbibing water to affect an osmotic pressure gradient across the barrierof the surrounding coating. Suitable osmogens include, but are notlimited to, inorganic salts, such as magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, and sodium sulfate; sugars, such asdextrose, fructose, glucose, inositol, lactose, maltose, mannitol,raffinose, sorbitol, sucrose, trehalose, and xylitol, organic acids,such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleicacid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamicacid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea;and mixtures thereof.

Osmotic agents of different dissolution rates may be employed toinfluence how rapidly the active ingredient(s) is initially deliveredfrom the dosage form. For example, amorphous sugars, such as MANNOGEM™EZ (SPI Pharma, Lewes, Del.) can be used to provide faster deliveryduring the first couple of hours to promptly produce the desiredtherapeutic effect, and gradually and continually release of theremaining amount to maintain the desired level of therapeutic orprophylactic effect over an extended period of time. In this case, theactive ingredient(s) is released at such a rate to replace the amount ofthe active ingredient metabolized and excreted.

The core may also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful in forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs, or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking Examples ofsuitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

Semipermeable membrane may also be a hydrophobic microporous membrane,wherein the pores are substantially filled with a gas and are not wettedby the aqueous medium but are permeable to water vapor, as disclosed inU.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeablemembrane are typically composed of hydrophobic polymers such aspolyalkenes, polyethylene, polypropylene, polytetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes.

The delivery port(s) on the semipermeable membrane may be formedpost-coating by mechanical or laser drilling. Delivery port(s) may alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports may be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the active ingredient(s) released and the releaserate can substantially by modulated via the thickness and porosity ofthe semipermeable membrane, the composition of the core, and the number,size, and position of the delivery ports.

The pharmaceutical compositions in an osmotic controlled-release dosageform may further comprise additional conventional excipients or carriersas described herein to promote performance or processing of theformulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra; Santus andBaker, J. Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J.Controlled Release 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients orcarriers. See, U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMTcontrolled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art,including direct compression, dry granulation, wet granulation, and adip-coating method.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),a hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients or carriers.

4.4.3. Multiparticulate Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form may be fabricated as a multiparticulate controlled releasedevice, which comprises a multiplicity of particles, granules, orpellets, ranging from about 10 μm to about 3 mm, about 50 μm to about2.5 mm, or from about 100 μm to about 1 mm in diameter. Suchmultiparticulates may be made by the processes known to those skilled inthe art, including wet- and dry-granulation, extrusion/spheronization,roller-compaction, melt-congealing, and by spray-coating seed cores.See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker:1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

Other excipients or carriers as described herein may be blended with thepharmaceutical compositions to aid in processing and forming themultiparticulates. The resulting particles may themselves constitute themultiparticulate device or may be coated by various film-formingmaterials, such as enteric polymers, water-swellable, and water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

4.4.4. Targeted Delivery

The pharmaceutical compositions provided herein may also be formulatedto be targeted to a particular tissue, receptor, or other area of thebody of the subject to be treated, including liposome-, resealederythrocyte-, and antibody-based delivery systems. Examples include, butare not limited to, U.S. Pat. Nos. 6,316,652; 6,274,552; 6,271,359;6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082;6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252;5,840,674; 5,759,542; and 5,709,874.

5. Methods of Use

In one embodiment, provided herein are methods for treating known orsuspected cyanide poisoning, which comprise administering to a subjecthaving or at risk for having cyanide poisoning, a therapeuticallyeffective amount of sodium thiosulfate provided herein. In oneembodiment, the subject is a mammal. In another embodiment, the subjectis a human.

In one embodiment, provided herein are methods for treating orpreventing platinum-induced ototoxicity, such as that associated withthe use of cisplatin or other platinum-containing medication, whichcomprise administering to a subject having or at risk for havingplatinum-induced ototoxicity, such as that associated with the use ofcisplatin or other platinum-containing medication, a therapeuticallyeffective amount of sodium thiosulfate provided herein. In oneembodiment, the subject is a mammal. In another embodiment, the subjectis a human.

In another embodiment, provided herein are methods for treating orpreventing platinum-induced nephtotoxicity, such as that associated withthe use of cisplatin or other platinum-containing medication, whichcomprise administering to a subject having or at risk for havingplatinum-induced nephtotoxicity, such as that associated with the use ofcisplatin or other platinum-containing medication, a therapeuticallyeffective amount of sodium thiosulfate provided herein. In oneembodiment, the subject is a mammal. In another embodiment, the subjectis a human.

In yet another embodiment, provided herein are methods for treating avascular calcification, including by not limited to atherosclerosis,which comprise administering to a subject having a vascularcalcification, including by not limited to atherosclerosis, atherapeutically effective amount of sodium thiosulfate provided herein.In one embodiment, the subject is a mammal. In another embodiment, thesubject is a human.

In certain embodiments, provided here are methods for treating conditionassociated with calciphylaxis, which comprise administering to a subjecthaving a condition associated with calciphylaxis, a therapeuticallyeffective amount of sodium thiosulfate provided herein. In oneembodiment, the subject is a mammal. In another embodiment, the subjectis a human.

In yet another embodiment, provided herein are methods for treating adermatological disease or a condition associated with the skin,including, but not limited to, tinea versicolor, bacterial infection ofthe skin, mycotic infection of the skin, viral infection of the skin,mycotic infection of the nails, bacterial infection of the nails, viralinfection of the nails, mycotic infection of the nailbeds, bacterialinfection of the nailbeds, viral infection of the nailbeds, psoriasis,scleroderma, inflammation of the skin, inflammation of the nails, andinflammation of the nailbeds, which comprise administering to a subjecthaving a dermatological disease or a condition associated with the skin,a therapeutically effective amount of sodium thiosulfate providedherein.

Depending on the condition, disorder, or disease, to be treated and thesubject's condition, the sodium thiosulfate provided herein may beadministered by oral, parenteral (e.g., intramuscular, intraperitoneal,intravenous, intracerebroventricular (ICV), intracistemal injection orinfusion, subcutaneous injection, or implant), inhalation, nasal,vaginal, rectal, sublingual, or topical (e.g., transdermal or local)routes of administration, and may be formulated, alone or together, insuitable dosage unit with pharmaceutically acceptable carriers,adjuvants and vehicles appropriate for each route of administration.

The dose may be in the form of one, two, three, four, five, six, or moresub-doses that are administered at appropriate intervals per day. Thedose or sub-doses can be administered in the form of dosage unitscontaining from about 10 ng to about 1000 g, from about 10 mg to about100 g, from about 500 mg to about 50 g, from about 1 g to about 25 g, orfrom about 5 g to about 12.5 g active ingredient(s) per dosage unit, andif the condition of the patient requires, the dose can, by way ofalternative, be administered as a continuous infusion.

In certain embodiments, an appropriate dosage level is about 0.001 toabout 100 g per kg patient body weight per day (g/kg per day), about0.01 to about 50 mg/kg per day, about 0.01 to about 25 mg/kg per day, orabout 0.05 to about 10 mg/kg per day, which may be administered insingle or multiple doses. A suitable dosage level may be about 0.01 toabout 100 mg/kg per day, about 0.05 to about 50 mg/kg per day, or about0.1 to about 10 mg/kg per day. Within this range the dosage may be about0.01 to about 0.1, about 0.1 to about 1.0, about 1.0 to about 10, orabout 10 to about 50 mg/kg per day.

6. Combination Therapy

The sodium thiosulfate provided herein may also be combined or used incombination with other therapeutic agents useful in the treatment and/orprevention of the diseases and conditions provided herein.

As used herein, the term “in combination” includes the use of more thanone therapy (e.g., one or more prophylactic and/or therapeutic agents).However, the use of the term “in combination” does not restrict theorder in which therapies (e.g., prophylactic and/or therapeutic agents)are administered to a subject with a disease or disorder. A firsttherapy (e.g., a prophylactic or therapeutic agent such as a compoundprovided herein) can be administered prior to (e.g., 5 minutes, 15minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks,4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantlywith, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, or 12 weeks after) the administration of a secondtherapy (e.g., a prophylactic or therapeutic agent) to the subject.Triple therapy is also contemplated herein.

As used herein, the term “synergistic” includes a combination of thesodium thiosulfate provided herein and another therapy (e.g., aprophylactic or therapeutic agent) which has been or is currently beingused to treat, prevent, or manage a disease or disorder, which is moreeffective than the additive effects of the therapies. A synergisticeffect of a combination of therapies (e.g., a combination ofprophylactic or therapeutic agents) permits the use of lower dosages ofone or more of the therapies and/or less frequent administration of saidtherapies to a subject with a disorder. The ability to utilize lowerdosages of a therapy (e.g., a prophylactic or therapeutic agent) and/orto administer said therapy less frequently reduces the toxicityassociated with the administration of said therapy to a subject withoutreducing the efficacy of said therapy in the prevention or treatment ofa disorder). In addition, a synergistic effect can result in improvedefficacy of agents in the prevention or treatment of a disorder.Finally, a synergistic effect of a combination of therapies (e.g., acombination of prophylactic or therapeutic agents) may avoid or reduceadverse or unwanted side effects associated with the use of eithertherapy alone.

The sodium thiosulfate provided herein can be administered incombination or alternation with another therapeutic agent. Incombination therapy, effective dosages of two or more agents areadministered together, whereas in alternation or sequential-steptherapy, an effective dosage of each agent is administered serially orsequentially. The dosages given will depend on absorption, inactivationand excretion rates of the drug as well as other factors known to thoseof skill in the art. It is to be noted that dosage values will also varywith the severity of the condition to be alleviated. It is to be furtherunderstood that for any particular subject, specific dosage regimens andschedules should be adjusted over time according to the individual needand the professional judgment of the person administering or supervisingthe administration of the compositions.

The compounds provided herein can be administered in combination withother classes of compounds, including, but not limited to, vasodilators,such as sodium nitrite; keratolytic agents, such as salicylic acid;endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon;thromboxane receptor antagonists, such as ifetroban; potassium channelopeners; thrombin inhibitors, such as hirudin; growth factor inhibitors,such as modulators of PDGF activity; platelet activating factor (PAF)antagonists; anti-platelet agents, such as GPIIb/IIIa blockers (e.g.,abciximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g.,clopidogrel, ticlopidine and CS-747), and aspirin; anticoagulants, suchas warfarin; low molecular weight heparins, such as enoxaparin; FactorVIIa Inhibitors and Factor Xa Inhibitors; renin inhibitors; neutralendopeptidase (NEP) inhibitors; vasopeptidase inhibitors (dual NEP-ACEinhibitors), such as omapatrilat and gemopatrilat; HMG CoA reductaseinhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin,NK-104 (a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522(also known as rosuvastatin, atavastatin, or visastatin); squalenesynthetase inhibitors; fibrates; bile acid sequestrants, such asquestran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors;MTP Inhibitors; calcium channel blockers, such as amlodipine besylate;potassium channel activators; alpha-adrenergic agents; beta-adrenergicagents, such as carvedilol and metoprolol; antiarrhythmic agents;diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide,hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,trichloromethiazide, polythiazide, benzothiazide, ethacrynic acid,ticrynafen, chlorthalidone, furosenide, muzolimine, bumetanide,triamterene, amiloride, and spironolactone; thrombolytic agents, such astissue plasminogen activator (tPA), recombinant tPA, streptokinase,urokinase, prourokinase, and anisoylated plasminogen streptokinaseactivator complex (APSAC); anti-diabetic agents, such as biguanides(e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulins,meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride,glyburide, and glipizide), thiozolidinediones (e.g., troglitazone,rosiglitazone, and pioglitazone), and PPAR-gamma agonists;mineralocorticoid receptor antagonists, such as spironolactone andeplerenone; growth hormone secretagogues; aP2 inhibitors;phosphodiesterase inhibitors, such as PDE III inhibitors (e.g.,cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, andvardenafil); protein tyrosine kinase inhibitors; antiinflammatories;antiproliferatives, such as methotrexate, FK506 (tacrolimus),mycophenolate mofetil; chemotherapeutic agents; immunosuppressants;anticancer agents and cytotoxic agents (e.g., alkylating agents, such asnitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, andtriazenes); antimetabolites, such as folate antagonists, purineanalogues, and pyrimidine analogues; antibiotics, such asanthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin;enzymes, such as L-asparaginase; farnesyl-protein transferaseinhibitors; hormonal agents, such as glucocorticoids (e.g., cortisone),estrogens/antiestrogens, androgens/antiandrogens, progestins, andluteinizing hormone-releasing hormone antagonists, and octreotideacetate; microtubule-disruptor agents, such as ecteinascidins;microtubule-stabilizing agents, such as pacitaxel, docetaxel, andepothilones A-F; plant-derived products, such as vinca alkaloids,epipodophyllotoxins, and taxanes; and topoisomerase inhibitors;prenyl-protein transferase inhibitors; and cyclosporins; steroids, suchas prednisone and dexamethasone; cytotoxic drugs, such as azathioprineand cyclophosphamide; TNF-alpha inhibitors, such as tenidap; anti-TNFantibodies or soluble TNF receptor, such as etanercept, rapamycin, andleflunimide; and cyclooxygenase-2 (COX-2) inhibitors, such as celecoxiband rofecoxib; and miscellaneous agents such as, hydroxyurea,procarbazine, mitotane, hexamethylmelamine, gold compounds, platinumcoordination complexes, such as cisplatin, satraplatin, and carboplatin.

The sodium thiosulfate provided herein can also be provided as anarticle of manufacture using packaging materials well known to those ofskill in the art. See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and5,033,252. Examples of pharmaceutical packaging materials include, butare not limited to, blister packs, bottles, tubes, inhalers, pumps,bags, vials, containers, syringes, and any packaging material suitablefor a selected formulation and intended mode of administration andtreatment.

Provided herein also are kits which, when used by the medicalpractitioner, can simplify the administration of appropriate amounts ofactive ingredients to a subject. In certain embodiments, the kitprovided herein includes a container and a dosage form of the sodiumthiosulfate provided herein.

In certain embodiments, the kit includes a container comprising a dosageform of the sodium thiosulfate provided herein, in a containercomprising one or more other therapeutic agent(s) described herein.

Kits provided herein can further include devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, needle-less injectors drip bags, patches,and inhalers. The kits provided herein can also include condoms foradministration of the active ingredients.

Kits provided herein can further include pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a solid form thatmust be reconstituted for parenteral administration, the kit cancomprise a sealed container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:aqueous vehicles, including, but not limited to, Water for InjectionUSP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles, including, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles,including, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The disclosure will be further understood by the following non-limitingexamples.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples, regardless of whether a particular abbreviation isspecifically defined, are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, butwithout limitation, the following abbreviations may be used in theexamples and throughout the specification: g (grams); mg (milligrams);mL (milliliters); μL (microliters); mM (millimolar); μM (micromolar);mmol (millimoles); eq. (equivalent); hr or hrs (hours); min (minutes).

For all of the following examples, standard work-up and purificationmethods known to those skilled in the art can be utilized. Unlessotherwise indicated, all temperatures are expressed in ° C. (degreesCentigrade). All reactions conducted at room temperature unlessotherwise noted. Methodologies illustrated in the following examples areintended to exemplify the applicable chemistry through the use ofspecific examples and are not indicative of the scope of the disclosure.

Example 1 Preparation of Pharmaceutical Grade Sodium ThiosulfatePentahydrate

Under nitrogen, 57 kilograms of sulfur and deionized water (799.1kilograms) were charged to an inerted 500 gallon reactor system with anOrion Ross combination pH probe. The slurry was stirred and 161.4kilograms of sodium sulfite was charged to the reactor. The reactor washeated to between 95 and 100° C. for 4 hours. The pH of the slurrywithin the reactor after 4 hours was 7.3. The reactor was cooled to20+/−5° C. The pH of the cooled slurry was 6.6. 300 grams of sodiumhydroxide 50 weight % solution was added to the reactor contents toincrease the pH of the slurry within the reactor to 7.4. The contents ofreactor were filtered through an Estrella filter. The resulting filtratewas distilled under vacuum at 50 to 100° C. to a specific gravity of1.40. Maintaining the temperature of the solution at 50+/−5° C., 300grams of activated carbon was added to the solution. The solution wasstirred for one hour and 3 minutes and subsequently filtered with a bagfilter and to remove the activated carbon. The filtered solution wascooled to 20+/−5° C. and 15 grams of sodium thiosulfate pentahydratecrystals were added to the solution. The solution was then cooled to5+/−5° C. and stirred for 15 hours and 2 minutes. The contents withinthe reactor consisting of both solids and liquid were filtered throughan Aurora filter under an inert environment. The mother liquor was usedto rinse solids from the walls of the reactor. Solids were loaded ontodrying trays and placed into a drying oven under full vacuum with anitrogen bleed for 8 hours at 35° C. Drying continued after 8 hoursuntil in-process testing confirmed that the water content (Loss onDrying) of the material was between 34.0 and 36.8%. The dried solid hada final mass of 112.5 kilograms (36% yield).

The analysis of sodium thiosulfate pentahydrate provided herein from thepurification procedure is summarized in Table 1.

TABLE 1 Analysis Testing Result USP Assay    100% HPIC Assay 98.7 SodiumComplies^(a) Thiosulfate Complies^(a) Reduction of Iodine TS to IodideColor was discharged Water Content (Loss on Drying)   36.4% Calcium(Ca)-ammonium oxalate TS No turbidity Appearance Colorless crystals OdorOdorless Appearance of a 10% solution at 25° C. Clear and colorless pHof 10% solution at 25° C.  6.6 Heavy Metals  <10 ppm Sulfide (as S) <0.001% Carbonate   0.01% Insoluble Matter  <0.005% Chloride   0.004%Lead  <0.001% Nitrogen Compounds (as N)  <0.002% Sulfite   0.01% Sulfate(as SO₄)   0.08% Iron by ICP-OES or equivalent  0.00019% Calcium byICP-OES or equivalent None detected Potassium by ICP-OES or equivalentNone detected Organic volatile impurities (Ethanol and Methanol) <300ppm ethanol; None detected - methanol Total non-purgeable organic carbonor equivalent  <2.6 ppm (NPOC) Mercury or ICP-OES or equivalent Nonedetected Aluminum or ICP-OES or equivalent  0.58 ppm Arsenic or ICP-OESor equivalent None detected Selenium ICP-OES or equivalent 0.000091%Total Aerobic Microbial Count <10 CFU/g Total Yeast and Mold Count <10CFU/g Bacterial Endotoxins <0.0015 EU/mg ^(a)The identification ofsodium and thiosulfate were determined using the identification tests,Method 191, as described in USP XXXII (2009).

Example 2 Method of Determining the Total Non-Purgeable Organic Carbonin Sodium Thiosulfate Pentahydrate

Total non-purgeable organic carbon (NPOC) was determined using anInnovOx laboratory TOC Analyzer (GE Analytical Instruments, Inc.,Boulder, Colo.). Water used for standard, reagent, and samplepreparation had total organic carbon (TOC) of no greater than 0.10 ppm.Phosphoric acid was ACS reagent grade. Sodium persulfate was obtainedfrom General Electric (GE Part # APK68050-01, Fairfield, Conn.). SucroseUSP was used as a reference standard. Compressed nitrogen has no greaterthan 1 ppm CO₂ and no greater than 1 ppm THC.

Phosphoric acid (6 N) used as acidification solution was prepared byadding approximately 100 mL of water to a 250 mL volumetric flask,followed by the slow addition of 100 mL of phosphoric acid and addingadditional water to make the final volume of 250 mL. Phosphoric acid(6%) solution was prepared by adding 120 mL of 6N phosphoric acidsolution to a 2,000 mL volumetric flask, and adding water to bring thevolume to 100 mL at room temperature.

Sodium persulfate solution (30%) used as an oxidizer was prepared byadding 150 0.1 g of sodium persulfate to a 500 mL volumetric flask, andadding additional water to make the final volume of 500 mL, after thesodium persulfate was dissolved. The solution was allowed to sit for 3days prior to use, and used within 14 days of the preparation.

The sucrose stock standard (250 ppm carbon based on 0.50 mg carbon/1.2mg sucrose) was prepared by dissolving 9 mg of sucrose in 15 mL ofwater. TOC standard (10 ppm) was prepared by adding 4 mL of the sucrosestock standard to a 100 mL volumetric flask, followed by the addition ofwater to bring the volume to 100 mL at room temperature. TOC standard (2ppm) was prepare by adding 10 mL of the 10 ppm TOC standard to a 50 mLvolumetric flask, followed by the addition of water to bring the volumeto 50 mL at room temperature. TOC standard (0.5 ppm) was prepare byadding 5 mL of the 10 ppm TOC standard to a 100 mL volumetric flask,followed by the addition of water to bring the volume to 100 mL at roomtemperature.

The sodium thiosulfate pentahydrate sample solution was prepared byadding 5.0 g of a sample into a 100 mL volumetric flask, followed by theaddition of 6% phosphoric acid solution to bring the volume to 100 mL atroom temperature. The sample solution was centrifuged for 15 min, andallowed to stand overnight to allow the precipitate to settle.

The InnovOx instrument was calibrated with 6% phosphoric acid solution(blank), and the 0.5 ppm, 2 ppm, and 10 ppm TOC standards, using theinstrument parameters as shown in Table 2.

TABLE 2 Protocol Name Sodium Thiosulfate pentahydrate Cal Number Points4 Range 0-1000 ppm Acid   0% Oxidizer 45.0% Sparge 4.0 min BlankCorrection Off Auto Dilution Off Cal Type Pt-Pt Replicates 7 Rejects 2

The calibration curve requirements were that i) the correlationcoefficient (r) of the average of the replicates must be no less than0.99; ii) the RSD for the 2 and 10 ppm TOC standards must be no greaterthan 15%; iii) the limit of quantitation (LOQ) must be no greater than 3ppm, which was calculated as follows:LOQ=(10)(A)(B)/(C−D)and iv) the limit of detection (LOD) must be no greater than 1 ppm,which was calculated as follows:LOD=(3)(A)(B)/(C−D)where:

A was the concentration of carbon in the 0.5 ppm TOC standard;

B was the standard deviation of the TOC concentration determined in theblank preparation;

C was the average TOC concentration determined in the 0.5 ppm TOCstandard; and

D is the average TOC concentration determined in the blank preparation.

Samples were analyzed using the following instrument parameters as shownin Table 3.

TABLE 3 Number Points 4 Range 0-1000 ppm Acid   0% Oxidizer 45.0% Sparge4.0 min Flush Dilution Blank Correction Off Calibration SodiumThiosulfate Pentahydrate Cal Replicates 6 Rejects 2

The 2 ppm TOC standard was run before and after each sample analysis.

The system suitability requirements were that i) the RSD for the 2 ppmTOC standard must be no greater than 15%; ii) the percentage oftheoretical response (% T) for the 2 ppm TOC standard determinationsmust be no less than 80% and no greater than 120%; which was calculatedas follows:% T=100×A/B;where:

A was the result determined by the analyzer (ppm); and

B was the 2 ppm standard TOC concentration (ppm);

iii) for any sample that had a sample response at or above the LOQ tofive times the LOQ, the RSD must be no greater than 25%; or for anysample that had a sample response more than five times the LOQ, the RSDmust be no greater than 15%.

The total non-purgeable organic carbon in each sample was calculated asfollows:NPOC=A×B/C;where:

A was the result determined by the analyzer (ppm);

B was sample dilution volume (mL); and

C was sample mass (g).

In calculating total non-purgeable organic carbon, if A is less than theLOD, A in the formula was replaced with LOD for calculation to providean upper limit for the total non-purgeable organic carbon value. If A isless than the LOQ, but more than the LOD, the total non-purgeableorganic carbon value as calculated provided an approximate value and theLOQ set an upper limit for the total non-purgeable organic carbon.

Example 3 Method of Determining Sulfide Impurity in Sodium ThiosulfatePentahydrate Drug Substance

This protocol describes the procedure for qualification of awet-chemistry test for detection of sulfide in sodium thiosulfatepentahydrate drug substance and drug product samples. The sulfideimpurity, if present in samples, is detected as lead(II) sulfide, whichforms gray precipitate. The method-detection-limit is set at 10 ppm or10 μg/g of sulfide, based on the drug product concentration of 250 mg/mLsodium thiosulfate pentahydrate in solution, and use of 1 mL of drugproduct for testing.

a. Protocol

NaOH (0.01 N) reagent was prepared by dissolving approximately 4.0 g ofsodium hydroxide (ACS reagent grade) in 1,000 mL of deionized water. Thesolution was further diluted from 10 mL to 100 mL volumetrically toyield 0.01 N sodium hydroxide solution. Alternatively, commercial 0.01 Nsodium hydroxide may also be used.

Lead nitrate reagent (1 mg/mL) was prepared by accurately weighing 40±2mg of lead nitrate (ACS reagent grade) and dissolving the lead nitratein 25 mL of deionized water.

Sodium sulfide standard (50 mg/L sulfide) was prepared by accuratelyweighing 37±2 mg of sodium sulfide into a 100-mL volumetric flask. Thesulfide was dissolved and diluted to the volume with 0.01 N sodiumhydroxide.

For a sample, a 250 mg/mL solution in deionized water was prepared.Samples were tested singularly, in 10-mL test tubes or 4-mL glass vialswith Teflon-lined caps. In parallel, test vials were prepared as shownin Table 4.

TABLE 4 Deionized Sulfide Sample Label Water Test Sample Standard Pb(II)Reagent Blank 1.0 mL None 0.0 μL 100 Standard 1.0 mL None  50 μL 100Sample None 1.0 mL 0.0 μL 100 Sample-Spike None 1.0 mL  50 μL 100

For quality control, the four test should meet the followingrequirements: i) the blank vial should be visibly clear and colorless;ii) the standard vial must have dark gray color or precipitate, clearlydistinguishable from the blank; iii) the specificity solutionscontaining sulfate, sulfite, and chloride must have lighter gray colorthan the standard vial, and white precipitate is anticipated; and iv)the sulfide-spikes of specificity solutions containing sulfate, sulfite,and chloride must have darker gray color than the correspondingun-spiked solutions.

b. Method Specificity

The requirements for specificity were: i) the blank vial should bevisibly clear and colorless; ii) the standard vial must have dark graycolor or precipitate, clearly distinguishable from the blank; iii) thespecificity solutions containing sulfate, sulfite, and chloride musthave lighter gray color than the standard vial, and white precipitate isanticipated; and iv) the sulfide-spikes of specificity solutionscontaining sulfate, sulfite, and chloride must have darker gray colorthan the corresponding un-spiked solutions. All the requirements setforth in the protocol were met.

Test solutions were prepared to contain 1 mg/mL individually, of sodiumsulfate, sodium sulfite, and sodium chloride. Duplicate vials of thesesolutions were tested to evaluate potential interference. In addition,these test solutions were individually test with sulfide spiking, inorder to evaluate interference to sulfide detection. The results aresummarized in Table 5. The sulfide standard was prepared at aconcentration of 50 mg/L sulfide, and lead nitrate reagent was preparedat a concentration of 1 g/L (Pb(II). The test solution color of gray ortan is accepted.

TABLE 5 Results for Method Specificity Test Vol. of Test Vol. of SulfideVol. of Lead(II) Test Solution Solution (mL) Standard (μL) Reagent (μL)Observations Blank, Water 1.0 0 100 Clear colorless solution 1.0 0 100Clear colorless solution Sodium Sulfate 1.0 0 100 Clear colorlesssolution 1.0 0 100 Clear colorless solution Sodium Sulfite 1.0 0 100Slightly cloudy, white precipitate 1.0 0 100 Slightly cloudy, whiteprecipitate Sodium Chloride 1.0 0 100 Clear colorless solution 1.0 0 100Clear colorless solution Standard (blank- 1.0 50 100 Clear tan solutionSpike) Sodium Sulfate- 1.0 50 100 Light tan solution, Spike darkerparticulate Sodium Sulfite- 1.0 50 100 Slightly cloudy tan Spikesolution, dark particulate Sodium 1.0 50 100 Light tan solutionChloride-Spike

The test method was shown to be specific to sulfide in the presence ofsulfate, sulfite, and chloride.

c. Limit of Detection

As shown in Tables 6 and 7, the presence of sulfide in the blank (water)or in the drug product sample (sodium thiosulfate pentahydrate) wasdetermined at 4 ppm and above with detection of tan color. According tothe protocol, the limit of detection of sulfide in sodium thiosulfatepentahydrate drug product was determined to be 4 ppm.

The limit of detection was determined to be 4 ppm, which was well belowthe limit (10 ppm).

TABLE 6 Vol. of Vol. of Vol. of Sample Deionized Vol. of Sulfide Lead(II) Label Water Sample Standard Reagent Observations Sample- 1.0 mL 0 0 μL 100 μL Clear colorless blank solution 2 ppm 1.0 mL 0 10 μL 100 μLClear, maybe Standard hint of tan 4 ppm 1.0 mL 0 20 μL 100 μL Clearsolution, Standard light tan color 5 ppm 1.0 mL 0 30 μL 100 μL Clearsolution, Standard tan color 8 ppm 1.0 mL 0 40 μL 100 μL Clear solution,Standard tan color 10 ppm 1.0 mL 0 50 μL 100 μL Clear solution, Standardtan color Sample- 0 1.0 mL  0 μL 100 μL Clear colorless blank solution 2ppm 0 1.0 mL 10 μL 100 μL Clear colorless Standard solution 4 ppm 0 1.0mL 20 μL 100 μL Clear solution, Standard light tan color 5 ppm 0 1.0 mL30 μL 100 μL Clear solution, Standard tan color 8 ppm 0 1.0 mL 40 μL 100μL Clear solution, Standard tan color 10 ppm 0 1.0 mL 50 μL 100 μL Clearsolution, Standard tan color

TABLE 7 Vol. of Vol. of Vol. of Sample Deionized Vol. of Sulfide Lead(II) Label Water Sample Standard Reagent Observations Sample- 1.0 mL 0 0 μL 100 μL Clear colorless blank solution 2 ppm 1.0 mL 0 10 μL 100 μLClear solution, Standard very light color 4 ppm 1.0 mL 0 20 μL 100 μLClear solution, Standard light tan color 5 ppm 1.0 mL 0 30 μL 100 μLClear solution, Standard light tan color 8 ppm 1.0 mL 0 40 μL 100 μLClear solution, Standard tan color 10 ppm 1.0 mL 0 50 μL 100 μL Clearsolution, Standard tan color Sample- 0 1.0 mL  0 μL 100 μL Clearcolorless blank solution 2 ppm 0 1.0 mL 10 μL 100 μL Clear solution,Standard very light color 4 ppm 0 1.0 mL 20 μL 100 μL Clear solution,Standard light tan color 5 ppm 0 1.0 mL 30 μL 100 μL Clear solution,Standard light tan color 8 ppm 0 1.0 mL 40 μL 100 μL Clear solution,Standard tan color 10 ppm 0 1.0 mL 50 μL 100 μL Clear solution, Standardtan color

Example 4 Method for Determination of Thiosulfate in Sodium ThiosulfatePentahydrate

The concentration of sodium thiosulfate pentahydrate in a drug productwas determined using ion chromatography with electrochemicalconductivity detection on a Dionex IonPac AS12A analytical column (P/N046034, Dionex Corporation, Sunnyvale, Calif.), eluted with 13.5 mMsodium carbonate (ACS reagent grade) and 1.5 mM sodium bicarbonate (ACSreagent grade) in deionized water at 1.5 mL/min with a detector range of50 μS for 15 min. The ion-exchange column was run at room temperaturewith suppressor current at 100 mA.

For mobile phase preparation, a stock sodium carbonate solution (500 mM)was prepared by adding 26.5 g of sodium carbonate (ACS reagent grade) toa 500 mL volumetric flask, followed by the addition of deionized waterto bring the volume to 500 mL at room temperature; and a stock sodiumbicarbonate solution (500 mM) was prepared by adding 10.5 g of sodiumbicarbonate (ACS reagent grade) to a 500 mL volumetric flask, followedby the addition of deionized water to bring the volume to 500 mL at roomtemperature A mobile phase was prepared by adding 54 mL stock sodiumcarbonate solution and 6 mL stock sodium bicarbonate solution to a 2 Lvolumetric flask, followed by the addition of deionized water to bringthe volume to 2 L at room temperature.

A stock sodium thiosulfate standard solution (1 g/L) was prepared byadding 0.10 g of sodium thiosulfate pentahydrate to a 100 mL volumetricflask, followed by the addition of deionized water to bring the volumeto 100 mL at room temperature. A sodium thiosulfate reference standardwas prepared by adding 10.0 mL of the stock sodium thiosulfate solutionto a 100 mL volumetric flask, followed by the addition of deionizedwater to bring the volume to 100 mL at room temperature. A linearitystandard was prepared by diluting the sodium thiosulfate referencestandard (12.5 mL) to 25.0 mL with deionized water.

Thiosulfate-containing samples were prepared in duplicate. First, astock sample solution was prepared by adding 2.0 mL of the sample to a100 mL volumetric flask, followed by the addition of deionized water tobring the volume to 100 mL at room temperature.

System suitability was determined by first injecting the sodiumthiosulfate reference standard, followed by an injection of deionizedwater, to ensure no carryover that may interfere with the analysis. Thesodium thiosulfate reference standard was then injected six times. Thepercent relative standard deviation (% RSD) of the peak area ofthiosulfate was calculated. The first injection was used to calculatethe tailing factor and number of theoretical plates according to Method621 USP XXXII (2009). The % RSD of the peak area for the initial sixinjections of the thiosulfate peak must be NMT 2.0%. The tailing factorfor the thiosulfate peak must be NMT 2.0. The number of theoreticalplates (N) for the thiosulfate must be NLT 3,000. The area % RSD for thesix injections plus each continuing calibration injections must be NMT3.0%.

The sodium thiosulfate reference standard was injected twice and thearea difference (%) between the duplicate injections was determined. The% difference between the duplicate injections should be NMT 2.0% and theerror of the assay value must be NMT 2.0%. The average area responsethus determined was used to calculate the concentration of the previoussix injections, and the difference in percentage of the concentrationthus determined from the actual concentration was determined.

The sample solution diluent was injected once to check carryover andother peaks arising from the diluent. The peak area response at theretention time of thiosulfate should be NMT 1% of the area response forthe sodium thiosulfate reference standard.

Linearity standard was injected twice. For the linearity standard, theaverage peak area must be between 47.0 and 53.0% of the average peakarea for the system suitability injections. For the linearity standard,the % difference between the duplication injections must be NMT 2.0%.

Each sample solution was injected in duplicate. The % difference betweenthe duplicate was calculated. The % difference between in sodiumthiosulfate assay concentrations between the duplicate preparations wasalso calculated.

The instrument was verified every six sample injections and after thefinal sample injection by reanalyzing the sodium thiosulfate referencestandard in duplicate. For each sample, the % difference between theduplication injections must be NMT 2.0%, and the % difference betweenthe assay concentrations of thiosulfate in duplicate preparations mustbe NMT 2%. The concentration of a sodium thiosulfate pentahydrate samplewas calculated based on its peak area in comparison with that of thesodium thiosulfate standard.

Example 5 Determination of Trace Levels of Carbonate in SodiumThiosulfate Pentahydrate

All glassware was thoroughly rinsed with deionized water at least threetimes. Glassware used for weighing can be oven-dried, and extreme weretaken when handling as not to contaminate the glassware with organicmatter. Glassware used for dilution only was pre-rinsed at least threetimes with acidific reagent water, which was prepared by addingapproximately 1 to 2 mL of concentrated phosphoric acid to 4,000 mLdeionized water, followed by thoroughly rinsing with deionized waterjust prior to use. When weighing, a sterile plastic spatula was usedinstead of a metal spatula to reduce potential contamination.

Sodium carbonate stock solution used for preparing carbonate standardswas prepared by dissolving 0.177 g of sodium carbonate (ACS reagentgrade) in 100.0 mL deionized water. Nominal concentration of carbonateis 1,000 mg/L, equivalent to 200 mg/L of carbon. A series of carbonatecalibration standards was prepared by pipetting 100, 200, 400, 800, and1,000 μL of sodium carbonate stock solution into separate 200 mLvolumetric flasks, followed by adding deionized water to bring thevolume to 200 mL at room temperature. Nominal concentrations are 0.5,1.0, 2.0, 4.0, and 5.0 mg/L of carbonate, respectively. Care was takento make sure all carbonate solutions were tightly sealed and stored in acool area away from excessive heat.

Samples were prepared by weighing accurately to the nearest 0.01 mg andtransferring an amount of the sample equivalent to less than 1.0 mg/L ofcarbon (5.0 mg/L carbonate) into a 100 mL volumetric flask. For a sodiumthiosulfate pentahydrate drug substance with limit of carbonate at≦0.01%, 1.00 g of the sample in 100 mL water would yield 1 mg/L ofcarbonate, equivalent to 0.2 mg/L carbon, when presented at 0.01%. Then,20 mL of deionized was added to the 100 mL volumetric flask to dissolvethe sample. The sample solution was titrated with 0.1 N iodine VS(approximately 40 mL) (cat. #318981, Sigma-Aldrich, St. Louis, Mo.)until a persistent yellow color is observed. Deionized water was addedto bring the volume to 100 mL at room temperature.

Total inorganic carbon, was determined using a Shimadzu TOC-V Analyzerin IC mode. In the IC mode, the sample was acidified in line withphosphoric acid to convert the inorganic carbon (carbonate andbicarbonate) to carbon dioxide, which was then routed to thenon-dispersive infrared detector for quantitation. Only pre-cleaned TOCvials were used on the analyzer and each vial was filled completely witheither standards or samples and left leave no head space in the vial.The vials were secured with caps.

Under standard set-up, three measurements were made for each vial(standard, sample, or blank). Three measurements constituted a singlerun. Three rums of blank (deionized water) were performed to ensure thatthe analyzer was equilibrated and the results were consistent.

One run of each calibration standards was performed. The % RSD andaverage area response from the three injections of each standard weredetermined. Linear regression of the average areas versus the standardconcentrations was performed to determine the slope, intercept, andcorrelation coefficient for the calibration standards. Blank wasincluded in the linear regression analysis, but no forcing through zero.One run was performed for each sample. The % RSD of the three injectionsand the average peak area was determined, from which the carbonateconcentration was calculated based on the calibration standards.

The analyzer was calibrated every six sample runs and after the finalsample injection by performing one run of blank, followed by one run ofthe 2.0 mg/L calibration standard. The % RSD of both and carbonaterecovery from the calibration standard curve were calculated.

For quality control, the area (response) % RSD of the three injectionsfor each standard must be no greater than (NMT) 10%. The calibrationcurve for carbonate must have a correlation coefficient of no less than(NLT) 0.995. The area % RSD of the initial blank and continuingcalibration blank injections must be no greater than (NMT) 15%. The area% RSD for continuing calibration standard (2.0 mg/L) injections must benot more than (NMT) 10%. The % Recovery of the 2.0 mg/L continuingcalibration standard must be 85% to 115%.

The percent relative standard deviation (% RSD) is the standarddeviation divided by the mean times 100.

Example 6 Pharmaceutical Formulation Comprising Sodium ThiosulfatePentahydrate

An illustrative injection, solution comprising pharmaceutical gradesodium thiosulfate pentahydrate is set forth in Table 8.

TABLE 8 Unit Unit Formulation Formulation Ingredient Function (per mL)(per 50 mL vial) Pharmaceutical Active 250.0 mg 12.5 g grade Sodiumpharmaceutical thiosulfate, USP ingredient Potassium Tonicity  4.40 mg 220 mg chloride, USP modifying agent Boric acid, NF Buffer  2.80 mg 140 mg Boric acid, NF pH adjustment qs to target pH qs to target pHSodium pH adjustment qs to target pH qs to target pH hydroxide, NF WFI,USP Solvent qs Qs Abbreviations: NF, National Formulary; qs, quantitysufficient; USP, United States Pharmacopeia; WFI, water for injection.

The examples set forth above are provided to give those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the claimed embodiments, and are not intended to limit thescope of what is disclosed herein. Modifications that are obvious topersons of skill in the art are intended to be within the scope of thefollowing claims. All publications, patents, and patent applicationscited in this specification are incorporated herein by reference as ifeach such publication, patent or patent application were specificallyand individually indicated to be incorporated herein by reference.

What is claimed is:
 1. A method for treating vascular calcification orcalciphylaxis, comprising administering to a subject having vascularcalcification or calciphylaxis, a therapeutically effective amount ofpharmaceutical grade sodium thiosulfate pentahydrate, wherein thepharmaceutical grade sodium thiosulfate pentahydrate contains no greaterthan about 10 ppm of non-purgeable organic carbon, contains no greaterthan about 0.05 ppm of mercury, contains no greater than about 2 ppm ofaluminum, contains no greater than about 0.003% by weight of selenium,contains no less than about 98% by weight and no greater than about 102%by weight of sodium thiosulfate on an anhydrous basis measured by ionchromatography, has a water content between 32% and 37% by weight, has aheavy metal content of no greater than about 10 ppm, contains no greaterthan about 200 ppm of chloride, contains no greater than about 0.001% byweight of sulfide, contains no greater than about 0.002% by weight ofiron, contains no greater than about 0.01% by weight of calcium,contains no greater than about 0.005% by weight of potassium, containsno greater than about 0.1% of sulfite, contains no greater than about0.5% of sulfate, contains no greater than about 3 ppm of arsenic,contains no greater than about 0.001% by weight of lead, has totalaerobic count of microbial load of no greater than about 100 CFU/g, hastotal yeast and mold count of no greater than about 20 CFU/g, containsno greater than about 0.02 EU/mg of bacterial endotoxins, contains nogreater than about 0.002% by weight of nitrogen compounds, contains nogreater than about 0.005% by weight of insoluble matter, contains nogreater than 0.01% by weight of residual anti-caking agent, and containsno greater than ICH Q3C (R3) limits of organic volatile impurities,wherein a 10% aqueous solution of the pharmaceutical grade sodiumthiosulfate pentahydrate at 25° C. is colorless and has a pH betweenabout 6.0 and about 8.0, and wherein the pharmaceutical grade sodiumthiosulfate pentahydrate is odorless crystals.
 2. The method of claim 1,wherein vascular calcification is treated.
 3. The method of claim 2,further comprising the administration of a diuretic, a renin inhibitor,a neutral endopeptidase inhibitor (NEP), a vasopeptidase inhibitor (dualNEP-ACE inhibitor), a HMG CoA reductase inhibitor, a bile sequestrant,anti-atherosclerotic agent, a calcium channel inhibitor, a potassiumchannel activator, an alpha-adrenergic agent, a beta-adrenergic agent,an antiarrhythmic agent, an ACAT inhibitor, a MTP inhibitor, avasodilator, a platelet activating factor (PAF) antagonist, ananti-platelet agent, a P2Y(AC) antagonist, aspirin, or an anticoagulant.4. The method of claim 3, wherein the diuretic is chlorothiazide,hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzothiazide, ethacrynic acid, ticrynafed,chlorothalidone, furosemide, muzolimine, bumetanide, triamterene,amiloride or spironoloactone.
 5. The method of claim 3, wherein thevasopeptidase inhibitor is omapatrilat or gemopatrilat.
 6. The method ofclaim 3, wherein the HMG CoA reductase inhibitor is pravastatin,lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin,nisvastatin, or nisbastatin), and ZD-4522 (also know as rosuvastatin,atavastatin, or visatatin).
 7. The method of claim 3, wherein the bilesequestrant is questran or niacin.
 8. The method of claim 3, wherein thecalcium channel blocker is amlodipine besylate.
 9. The method of claim3, wherein the beta-adrenergic agent is carvedilol or metoprolol. 10.The method of claim 3, wherein the vasodilator is a phosphodiesteraseinhibitor, or sodium nitrite.
 11. The method of claim 3, wherein thephosphodiesterase inhibitor is cilostazol, sildenafil, tadalafil, orvardenafil.
 12. The method of claim 3, wherein the anti-platelet agentis abciximab, eptifibatide, or tirofiban.
 13. The method of claim 3,wherein the P2Y(AC) antagonist is clopidogrel, itclopidine or CS-747.14. The method of claim 3, wherein the anticoagulant is wafarin, a lowmolecular weight heparin, a Factor VIIa inhibitor, or a Factor Xainhibitor.
 15. The method of claim 14, wherein the low molecular weightheparin is enoxaparin.
 16. The method of claim 1, wherein calciphylaxisis treated.
 17. The method of claim 16, further comprising theadministration of a hormonal agent, a diuretic or an anti-diabeticagent.
 18. The method of claim 17, wherein the diuretic ischlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzothiazide, ethacrynic acid, ticrynafed,chlorothalidone, furosemide, muzolimine, bumetanide, triamterene,amiloride or spironoloactone.
 19. The method of claim 17, wherein theanti-diabetic agent is a biguanide, a glucosidase inhibitor, insulin, ameglitinide, a sulfonylurea, a thiozolidinediones, a PPAR-gammaagnonist, metformin, acarbose, repaglinide, flimepiride, glyburide,glipizide, troglitazone, rosiglitazone or pioglitazone.